Activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase 1/2

7439-92-1

WABPQHHGFIMREM-UHFFFAOYSA-N

Lead

Pb Blei in massiver form(nicht pulver) Blei(pulver) C.I. Pigment Metal 4 Lead element Lead Flake LEAD INGOT Lead metal Plomb(poudre) Plumbum Rough lead bullion

DTXSID2024161

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

Colloidal manganese Cutaval Manganese element Manganese fulleride Manganese metal alloy Manganese-55 manganeso

DTXSID2024169

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

CL:0000127

CL astrocyte

CHEBI:29108

CHEBI calcium(2+)

CHEBI:26523

CHEBI reactive oxygen species

GO:0016301

GO kinase activity

VT:0010499

VT calcium amount

GO:0007612

GO learning

GO:0007613

GO memory

MP:0002229

MP neurodegeneration

GO:1903409

GO reactive oxygen species biosynthetic process

GO:0006915

GO apoptotic process

WIKI increased

WIKI decreased

Heavy metals (cadmium, lead, copper, iron, nickel)

2021-10-25T03:21:10

Lead

2016-11-29T18:42:26

Arsenic

2021-04-27T00:15:21

Cadmium

2017-10-25T08:33:12

Manganese

2022-02-04T14:47:23

Uranium

2021-08-05T14:28:50

Nanoparticles and Micrometer Particles

2022-02-04T13:43:43

Sars-CoV-2 Virus from the coronaviridae family related to SARS-CoV, 229E, NL63, OC43, HKU1 and MERS.

Transmitted by aerosols

2021-02-23T04:50:40

2022-09-09T05:09:36

Chemical

2017-02-07T13:22:42

SARS-CoV

2020-03-01T10:42:46

Virus

2018-05-29T07:10:01

10116

NCBI Rattus norvegicus

10090

NCBI Mus musculus

9606

NCBI Homo sapiens

WikiUser_29

Invertebrates

WikiUser_28

Vertebrates

WCS_9606

common toxicological species human

10116

NCBI rat

WCS_7227

common ecological species fruit fly

WCS_7955

common ecological species zebrafish

WCS_160004

common ecological species gastropods

10090

NCBI mouse

6239

NCBI Caenorhabditis elegans

Activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase 1/2

Activation of MEK, ERK1/2

Molecular

ERK1 and ERK2 are proteins of 43 and 41 kDa that are nearly 85% identical overall, with much greater identity in the core regions involved in binding substrates (Boulton et al., 1990; 1991). The two phosphoacceptor sites, tyrosine and threonine, which are phosphorylated to activate the kinases, are separated by a glutamate residue in both ERK1 and ERK2 to give the motif TEY in the activation loop (Payne et al., 1991). Both are ubiquitously expressed, although their relative abundance in tissues is variable. For example, in many immune cells ERK2 is the predominant species, while in several cells of neuroendocrine origin they may be equally expressed (Gray Pearson and others 2001). They are stimulated to some extent by a vast number of ligands and cellular perturbations, with some cell type specificity (Lewis et al., 1998). In fibroblasts (the cell type in which the generalizations about their behavior and functions have been developed) they are activated by serum, growth factors, cytokines, certain stresses, ligands for G protein-coupled receptors (GPCRs), and transforming agents, to name a few (Gray Pearson and others 2001). They are highly expressed in postmitotic neurons and other highly differentiated cells (Boulton et al., 1991). In these cells they are often involved in adaptive responses such as long-term potentiation (English and Sweatt 1996; Atkins et al., 1998; Rossi-Arnaud et al., 1997).

Western blotting and immunoblotting.

UBERON:0000955

UBERON brain

CL:0000127

CL astrocyte

Moderate Mixed

Moderate

Adult

Moderate Moderate Moderate

Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD 1998 The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1 :602 –609 Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD 1991 ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65 :663 –675 Boulton TG, Yancopoulos GD, Gregory JS, Slaughter C, Moomaw C, Hsu J, Cobb MH 1990 An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249 :64 –67 English JD , Sweatt JD 1996 Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. J Biol Chem 271 :24329 –24332 Gray Pearson and others, Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions, Endocrine Reviews, Volume 22, Issue 2, 1 April 2001, Pages 153–183, https://doi.org/10.1210/edrv.22.2.0428 Lewis TS, Shapiro PS, Ahn NG 1998 Signal transduction through MAP kinase cascades. Adv Cancer Res 74 :49 –139 Payne DM, Rossomando AJ, Martino P, Erickson AK, Her J-H, Shananowitz J, Hunt DF, Weber MJ, Sturgill TW 1991 Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J 10 :885 –892 Rossi-Arnaud C, Grant SG, Chapman PF, Lipp HP, Sturani E, Klein R 1997 A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390 :281 –286 AOPWiki 2023-05-25T17:12:40

2023-07-28T09:33:09

Increase, intracellular calcium

Cellular

Calcium is arguably the most versatile and important intracellular messenger in neurons (Berridge et al., 2000). Interestingly, although calcium may often promote neuronal death, it can also activate pathways that promote survival. For example, calcium can promote survival through a pathway involving activation of protein kinase B (PKB/Akt) by calcium/calmodulin-dependent protein kinase (Yano et al., 1998). Calcium is a prominent regulator of cellular responses to stress, activating transcription through the cyclic-AMP response element-binding protein (CREB), which can promote neuron survival in experimental models of developmental cell death (Hu et al., 1999). Calcium can also activate a rapid neuroprotective signalling pathway in which the calcium-activated actin-severing protein gelsolin induces actin depolymerization, resulting in suppression of calcium influx through membrane NMDA (N-methyl-d-aspartate) receptors and voltage-dependent calcium channels (Furukawa et al., 1997). This may occur through intermediary actin-binding proteins that interact with NMDA receptor and calcium channel proteins. Finally, signals such as calcium and secreted amyloid precursor protein-α (sAPP-α), which increase cyclic GMP production, can induce activation of potassium channels and the transcription factor NF-κB, and thereby increase resistance of neurons to excitotoxic apoptosis (Furukawa et al., 1996).

An increase in [Ca2+]i was measured using Fluo3 AM as an indicator dye after the addition of metals (single or in mixture) to the culture wells following an optimized protocol (Arey et al., 2022). The fluorescent signals were read by fluorescence imaging plate reader Synergy HT (BioTek, Winooski, VT) (Rai and others 2010). Briefly, Ca2+ levels in human astrocytes were monitored by fluorescence microscopy using the Ca2+ indicator fluo-4. Slices were incubated with fluo-4-AM (2–5 µL of 2 mM dye were dropped over the tissue, attaining a final concentration of 2–10 µM and 0.01% of pluronic) and Sulforhodamine 101 (100 µM) for 30–60 min at room temperature (Navarrete and others 2013). In these conditions, most of the Fluo-4-loaded cells were astrocytes as indicated by their SR101 staining (Nimmerjahn et al., 2004; Dombeck et al., 2007; Kafitz et al., 2008; Takata and Hirase 2008), and confirmed in some cases by their electrophysiological properties. Astrocytes were imaged with an Olympus FV300 laser-scanning confocal microscope or a CCD camera (Retiga EX) attached to the Olympus BX50WI microscope (Navarrete and others 2013). Diversity of endogenous Ca2+ activity in a mature hippocampal astrocyte in situ: Ca2+ signals in cell body and processes are different. (A) Cumulative Ca2+ activity recorded in an astrocyte over a 165 s period revealed by the calcium indicator Fluo4-AM. The visible boundaries of the astrocyte are shown in white. Note the different intensities of spatially- confined local activity in the astrocyte cell body (s), primary process (p1) stemming from the soma and secondary processes (p2) branching from a primary process. Intensity of the normalized cumulative activity is expressed in arbitrary units (a.u.) and shown in pseudocolour, from dark (lowest) to white (highest). (B) Frequency map of the Ca2+ activity in the astrocyte during the 165 s period as in A. Activity is measured in individual pixels, expressed in mHz and color-coded from black (never active) to dark red (frequently active). Most of the activity is within the white boundaries and the most frequently active pixels are in defined small regions (arrowheads) of the primary and secondary processes (30 mHz), whereas pixels of the soma are less active (~10 mHz) (Volterra et al., 2014).  Free intracellular calcium ions were measured using the fluorescent calcium indicator FLUO-3/AM (Molecular probes, Eugene, OR, USA). Cells (4 × 104 cells/cm2) were seeded in 24-well plates for 24 h to reach 60%–70%, and then treated for 24 h with As(III) (0.5 and 1 mg/l), or coexposed to As(III) (1 mg/l) and F (2.5, 5, and 10 mg/l). After treatment, supernatant was collected and combined with trypsinized cells. Pelleted samples were resuspended in 500 μl of FLUO-3/AM (4 μmol/l) and incubated at 37 °C for 30 min. After centrifugation, cells were washed with HBSS (Hank's Buffered Salt Solution, Sigma), made up to 400 μl with HBSS and analyzed by flow cytometry. The signal from FLUO-3/AM bound to Ca2+ was recorded using the Fl-1 channel (Rocha et al., 2011). Fluo-4/AM was used as an intracellular free Ca2+ fluorescent probe to analyze [Ca2+]i in Cd-exposed cerebral cortical neurons. In short, the harvested cells were incubated with Fluo-4/AM (5 µmol/L final concentration) for 30 min at 37°C in the dark, washed with PBS, and analyzed on a BD-FACS Aria flow cytometry. Intracellular [Ca2+]i levels were represented by fluorescent intensity. Fluorescent intensity was recorded by excitation at 494 nm and emission at 516 nm. The data were analyzed by Cell Quest program (Becton Dickinson), and the mean fluorescence intensity was obtained by histogram statistics (Yuan et al., 2013).

UBERON:0000955

UBERON brain

CL:0000000

CL cell

Moderate Mixed

Moderate

Adult, reproductively mature

Moderate

Birth to < 1 month

Moderate Moderate

Arey BJ Seethala R Ma Z Fura A Morin J Swartz J Vyas V Yang W Dickson JK JrFeyen JH A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo Endocrinology 2005 146 2015 2022 Asit Rai and others, Characterization of Developmental Neurotoxicity of As, Cd, and Pb Mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions, Toxicological Sciences, Volume 118, Issue 2, December 2010, Pages 586–601, https://doi.org/10.1093/toxsci/kfq266 Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signaling. Nature Rev. Mol. Cell Biol. 1, 11– 21 (2000). Dombeck DA, Khabbaz AN, Collman F, Adelman TL, Tank DW. Imaging large-scale neural activity with cellular resolution in awake, mobile mice, Neuron, 2007, vol. 56 (pg. 43-57) Furukawa, K. et al. The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J. Neurosci. 17, 8178– 8186 (1997). Furukawa, K., Barger, S. W., Blalock, E. M. & Mattson, M. P. Activation of K+ channels and suppression of neuronal activity by secreted β-amyloid-precursor protein. Nature 379, 74–78 (1996). Hu, S. C., Chrivia, J. & Ghosh, A. Regulation of CBP-mediated transcription by neuronal calcium signaling. Neuron 22, 799– 808 (1999). Kafitz KW, Meier SD, Stephan J, Rose CR. Developmental profile and properties of sulforhodamine 101-labeled glial cells in acute brain slices of rat hippocampus, J Neurosci Methods, 2008, vol. 169 (pg. 84-92) Marta Navarrete and others, Astrocyte Calcium Signal and Gliotransmission in Human Brain Tissue, Cerebral Cortex, Volume 23, Issue 5, May 2013, Pages 1240–1246, https://doi.org/10.1093/cercor/bhs122 Nimmerjahn A, Kirchhoff F, Kerr JN, Helmchen F. Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo, Nat Methods, 2004, vol. 1 (pg. 31-37) R.A. Rocha, J.V. Gimeno-Alcañiz, R. Martín-Ibañez, J.M. Canals, D. Vélez, V. Devesa, Arsenic and fluoride induce neural progenitor cell apoptosis, Toxicology Letters, Volume 203, Issue 3, 2011, Pages 237-244, ISSN 0378-4274, https://doi.org/10.1016/j.toxlet.2011.03.023. Takata N, Hirase H. Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo., PLoS ONE, 2008, vol. 3 pg. e2525 Volterra, Andrea, Nicolas Liaudet, and Iaroslav Savtchouk. "Astrocyte Ca2+ signalling: an unexpected complexity." Nature Reviews Neuroscience 15.5 (2014): 327-335. Yano, S., Tokumitsu, H. & Soderling, T. R. Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Nature 396, 584–587 (1998). Yuan Y, Jiang C-y, Xu H, Sun Y, Hu F-f, Bian J-c, et al. (2013) Cadmium-Induced Apoptosis in Primary Rat Cerebral Cortical Neurons Culture Is Mediated by a Calcium Signaling Pathway. PLoS ONE 8(5): e64330. https://doi.org/10.1371/journal.pone.0064330 AOPWiki 2017-04-13T15:27:51

2023-07-21T16:26:34

Increase, Mitochondrial Dysfunction

Increase, Mt Dysfunction

Cellular

Mitochondria are organelles found in all eukaryotic cells, crucial to the cellular consumption of oxygen, production of energy through the generation of ATP during oxidative phosphorylation, and regulation of cell death pathways (Alberts et al., 2014). The mitochondria are responsible for reduction of oxygen into water via the action of cytochrome c oxidase and other redox enzymes which transfer single electrons to oxygen and partially reduce it. The electron transfer is coupled with H+ ion transport across a membrane, producing the ion gradient that powers ATP synthesis (Alberts et al., 2014; Adiele et al., 2012). Under normal metabolic function, approximately 1-2% of the oxygen reduced by mitochondria converts into reactive oxygen species (ROS; such as superoxide, hydrogen peroxide, or hydroxyl radicals) at intermediate steps of the respiratory chain, as a result of electron transport (Kowaltowski and Vercesi, 1998; Volka et al., 2005; Li et al., 2003). This consistent and regular production of ROS and their signalling functionality at regulated levels contrasted with their harmful effects at high concentrations, justify the presence of antioxidant systems to regulate these processes. Mitochondrial dysfunction, the loss of function or efficiency of oxidative phosphorylation, can be caused by a variety of factors and be apparent in a number of measurable ways. Some pathways of mitochondrial damage include: direct inhibition of mitochondrial proteins, indirect inhibition in upstream processes that affect mitochondrial metabolism, and indirect metabolic inhibition by ROS and physical damage to mitochondria. Dysfunction can be characterized through indicators of proton gradient loss, complex inhibition, or respiratory impairment such as mitochondrial permeability transition increase, mitochondrial membrane potential decrease, and ATP production (Shaki et al., 2013; Kruiderig et al., 1997). Any mitochondrial dysfunction impairs electron transfer and ATP production, which leads to deviation of electrons from their normal pathway in the electron transport chain (ETC), and increased ROS production. This, in turn, results in oxidative stress, mitochondrial permeability transition, and deregulation of cellular Ca2+ homeostasis (Nicholson, 2014; Shaki et al., 2013). Calcium, an imperative divalent cation to mitochondrial function, can be present at unsustainable levels due to increasing Ca2+ uptake, related to ROS generation and oxidative stress (reviewed Mei et al., 2013; Wang and Qin, 2010). Ca2+ accumulation and oxidative stress due additional ROS can trigger the opening of mitochondrial permeability transition pore (MPTP) by perturbing the osmolarity of mitochondria, disturbing Calcium homeostasis (Orrenius et al., 2015; Roos et al., 2012). The opening of the MPTP is a Ca2+-dependent process, that along with free proton movement collapses the mitochondrial membrane potential (MPP), halting ATP synthesis (Orrenius et al., 2015). ROS produced by the mitochondria can oxidize proteins and induce lipid peroxidation, compromising the barrier properties of the mitochondrial membrane (Orrenius et al., 2015) and therefore the proton gradient and ATP production. Respiration can also be impaired through mitochondrial DNA damage and increased permeability transition of the membrane as the mitochondrial inner membrane loses its impermeability to ions and other small molecules (up to a molecular weight of approximately 2kDa), this is loss of MPP and therefore proton gradient loss (Nicotera et al., 1998). Cytochrome c release is a major indicator of mitochondrial dysfunction as a combined result of a compromised mitochondrial membrane due to lipid peroxidation and the opening of the MPTP, and is commonly seen as an endpoint to mitochondrial toxicity (Chen et al., 2000). Mitochondrial damage can also be defined by loss of protein import and biosynthesis, as well as loss of mitochondrial motility as a result of failure to re-localize to sites with increased energy demands. <h3>Metal-induced Mitochondrial Dysfunction</h3> Mitochondria are an important site of Ca2+ regulation and storage, taking up Ca2+ ions electrophoretically from the cytosol through a Ca2+ uniporter, which can then accumulate in the mitochondria (Roos et al., 2012; Orrenius et al., 2015). Similarities between calcium and metals, such as cadmium and lead, makes the entrance and accumulation of these metals into the mitochondria via calcium metals possible by mode of molecular mimicry (Mathews et al., 2013; Adiele et al., 2012). The outer mitochondrial membrane also contains the divalent metal transporter (DMT1), which allows for mitochondrial uptake of divalent metals such as Fe and Mn. When cells are under heavy metal-induced stress, DMT has been shown to be overexpressed in the mitochondrial membrane, making the mitochondria targets of metal toxicity and accumulation. Heavy metal exposure in aerobic organisms increases ROS formation through redox cycling, where metals with different valence states (Fe, Cu, Cr, etc.) directly produce ROS as they are reduced by cellular antioxidants and then react with oxygen (Shaki et al., 2012; Shaki et al., 2013; Pourahmad et al., 2006; Santos et al., 2007). The production of highly reactive hydroxyl radicals under mitochondrial oxidative stress and in the presence of transition metals occurs via the Fenton reaction or Haber-Weiss reaction (Hancock et al., 2001; Valko et al., 2005; Adam-Vizi et al., 2010). Metals and ROS are capable of damaging mitochondrial DNA as well as mechanisms of DNA repair and proliferation arrest (Valko et al., 2005). Metals and ROS have the potential to directly damage mitochondrial membranes and structure by binding to and oxidizing membrane lipids and proteins. This structural damage can collapse the MMP and lead to the opening of the MPTP (Orrenius et al., 2015; Roos et al., 2012; Pourahmad et al., 2006). Uranium and mercury, for example, have both been shown to directly inhibit the mitochondrial electron transport chain and interfere with ATP production (Shaki et al., 2012; Roos et al., 2012). Furthermore, as previously mentioned, metals have been shown to inhibit ROS-detoxifying enzymes. By binding to these enzymes, metals can inhibit their antioxidant functions, and cause an accumulation of ROS and increased synthesis of more antioxidant enzymes in order to combat the oxidative stress (Blajszczak and Bonini, 2017).

<table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <tbody> <tr> <td>Assay - What is being Measured</td> <td>Description</td> <td>Dose Range Studied</td> <td>Assay Length / Ease of use, accuracy</td> </tr> <tr> <td> <div> <div>Rhodamine 123 Assay</div> Measuring Mitochondrial membrane potential (MMP) and its collapse  (Shaki et al., 2012) </div> </td> <td> <div>Mitochondrial uptake of cationic fluorescent dye, rhodamine 123, is used for estimation of mitochondrial membrane potential. The fluorescence was monitored using Schimadzou RF-5000U fluorescence spectrophotometer at the excitation and emission wavelength of 490 nm and 535 nm, respectively. </div> </td> <td>50, 100 and 500 μM of uranyl acetate</td> <td> Short / easy Medium accurancy </td> </tr> <tr> <td> <div> TMRE fluorescence Assay Measuring Mitochondrial permeability transition pore (MPTP) opening (Huser et al., 1998) </div> </td> <td>Laser scanning confocal microscopy in combination with the potentiometric fluorescence dye tetramethylrhodamine ethyl ester to monitor relative changes in membrane potential in single isolated cardiac mitochondria. The cationic dye distributes across the membrane in a voltage-dependent manner. Therefore, the large potential gradient across the inner mitochondrial membrane results in the accumulation of the fluorescent dye within the matrix compartment. Rapid depolarizations are caused by the opening of the transition pore.</td> <td>1 µM cyclosporin A</td> <td> Short / easy Low accurancy </td> </tr> <tr> <td> <div>GSH / GSSG Determination Assay</div> Measuring  cellular glutathione (GSH) status; ratio of GSH/GSSG (Owen & Butterfield, 2010; Shaki et al., 2013) </td> <td>GSH and GSSG levels are determinted biochemically with DTNB (Ellman’s reagent). The developed yellow color was read at 412 nm on a spectrophotometer.</td> <td>100 µM uranyl acetate</td> <td> Short / easy Low accurancy </td> </tr> <tr> <td> TBARS Assay Quantification of lipid peroxidation (Yuan et al., 2016) </td> <td>MDA content, a product of lipid peroxidation, was measured using a thiobarbituric acid reactive substances (TBARS) assay. Briefly, the kidney cells were collected in 1 ml PBS buffer solution (pH 7.4) and sonicated. MDA reacts with thiobarbituric acid forming a colored product which can be measured at an absorbance of 532 nm.</td> <td>200, 400, 800 µM uranyl acetate</td> <td> Medium / medium High accurancy </td> </tr> <tr> <td> <div>Aequorin-based bioluminescence assay</div> Increase in mitochondrial Ca2+ influx (Pozzan & Rudolf, 2009) </td> <td>Together with GFP, the aequorin moiety acts as Ca2+ sensor in vivo, which delivers emission energy to the GFP acceptor molecule in a BRET (Bioluminescence Resonance Energy Transfer) process; the Ca2+ can then be visualized with fluorescence microscopy.</td> <td> </td> <td> Short / easy Low accurancy </td> </tr> <tr> <td> <div>Western blot & immunostaining analyses</div> Measuring cytochrome c release (Chen et al., 2000)</td> <td>Examining the redistribution of Cyto c in cytosolic and mitochondrial cellular fractions. Cells are homogenized and centrifuged, then prepared for immunoblots. Cellular fractions were washed in PBS and lysed in 1% NP-40 buffer. Cellular proteins were separated by SDS–PAGE, transferred onto nitrocellulose membranes, probed using immunoblot analyses with antibodies specific to cyto c (6581A for Western and 65971A for immunostaining; Pharmingen)</td> <td> </td> <td> Short / easy Medium accurancy </td> </tr> <tr> <td> Quantikine Rat/Mouse Cytochrome c Immunoassay Measuring cytochrome c release (Shaki et al., 2012) </td> <td>Cytochrome C release was measured a monoclonal antibody specific for rat/mouse cytochrome c was precoated onto the microplate. Seventy-five microliter of conjugate (containing mono- clonal antibody specific for cytochrome c conjugated to horseradish peroxidase). After 2 h of incubation, the substrate solution (100 μl) was added to each well and incubated for 30 min. After 100 μl of the stop solution was added to each well; the optical density of each well was determined by the aforementioned microplate spectrophotometer set to 450 nm.</td> <td> </td> <td> Short / easy Low accurancy </td> </tr> <tr> <td> <div>Membrane potential and cell viability – Flow Cytometry</div> <div>Measuring cytochrome c release</div> (Kruiderig et al., 1997) </td> <td>“Dc and viability were determined by analyzing the R123 and propidium iodide fluorescence intensity with a FACScan flow cytometer (Becton Dickinson, San Jose, CA) equipped with an argon laser, with the Lysis software program (Becton Dickinson). R123 is a cationic dye that accumulates in the negatively charged inner side of the mitochondria. When the potential drops, less R123 accumulates in the mitochondria, which results in a lower fluorescence signal. The potential was measured as follows: at the indicated times, a 500-ml sample of the cell suspension was taken and transferred to an Eppendorf minivial. To this sample, 100 ml of 6 mM R123 in buffer D was added. After incubation for 10 min at 37°C, the cell suspension was centrifuged for 5 min at 80 3 g. The cell pellet was resuspended in 200 ml of buffer D, containing 0.2 mM R123 and 10 mM propidium iodide, to prevent loss of R123 and to stain nonviable cells, respectively. The samples were transferred to FACScan tubes and analyzed immediately. Analysis was performed at a flow rate of 60 ml/min. R123 fluorescence was detected by the FL1 detector with an emission detection limit below 560 nm. Propidium iodide fluorescence was detected by the FL3 detector, with emission detection above 620 nm. Per sample 3,000 to 5,000 cells were counted (Van de Water et al., 1993)”</td> <td> </td> <td> Short / easy Medium accurancy </td> </tr> </tbody> </table>

Mitochondrial dysfunction can occur in any eukaryotic cell.

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

High High Adam-Vizi, V., & Starkov, A. A. (2010). Calcium and mitochondrial reactive oxygen species generation: How to read the facts. Journal of Alzheimer's Disease : JAD, 20 Suppl 2, S413-S426. doi:10.3233/JAD-2010-100465 Adiele, R. C., Stevens, D., & Kamunde, C. (2012). Differential inhibition of electron transport chain enzyme complexes by cadmium and calcium in isolated rainbow trout (oncorhynchus mykiss) hepatic mitochondria. Toxicological Sciences, 127(1), 110-119. doi:10.1093/toxsci/kfs091 Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2014). Molecular biology of the cell. New York: Garland Science. Retrieved from <a href="https://www.ncbi.nlm.nih.gov/books/NBK21054/" style="color:blue; text-decoration:underline" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK21054/</a> Belyaeva, E. A., Sokolova, T. V., Emelyanova, L. V., & Zakharova, I. O. (2012). Mitochondrial electron transport chain in heavy metal-induced neurotoxicity : Effects of cadmium , mercury , and copper. Thescientificworld, 2012, 1-14. doi:10.1100/2012/136063 Blajszczak, C., & Bonini, M. G. (2017). Mitochondria targeting by environmental stressors: Implications for redox cellular signaling. Toxicology, 391, 84-89. doi:10.1016/j.tox.2017.07.013 Buelna-Chontal, M., Franco, M., Hernandez-Esquivel, L., Pavon, N., Rodriguez-Zalvala, J. S., Correa, F., . . . Chavez, E. (2017). CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction. Cell Biology International, 41, 1356-1366. doi:10.1002/cbin.10871 Chen, Q., Gong, B., & Almasan, A. (2000). Distinct stages of cytochrome c release from mitochondria: Evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis. Cell Death and Differentiation, 7(2), 227-233. doi:10.1038/sj.cdd.4400629 Görlach, A., Bertram, K., Hudecova, S., & Krizanova, O. (2015). Calcium and ROS: A mutual interplay. Redox Biology, 6, 260-271. doi:doi:10.1016/j.redox.2015.08.010 Hancock, J. T., Desikan, R., & Neill, S. J. (2001). Role of reactive oxygen species in cell signalling pathways. Biochemical Society Transactions, 29(Pt 2), 345-350. doi:10.1042/0300-5127:0290345 [doi] Hao, Y., Huang, J., Liu, C., Li, H., Liu, J., Zeng, Y., . . . Li, R. (2016). Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity. Scientific Reports, doi:10.1038/srep38942 Hao, Y., Ren, J., Liu, C., Li, H., Liu, J., Yang, Z., . . . Su, Y. (2014). Zinc protects human kidney cells from depleted uranium induced apoptosis. Basic & Clinical Pharmacology & Toxicology, 114, 271-280. doi:10.1111/bcpt.12167 Huerta-García, E., Perez-Arizti, J. A., Marquez-Ramirez, S. G., Delgado-Buenrostro, N. L., Chirino, Y. I., Iglesias, G. G., & Lopez-Marure, R. (2014). Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells. Free Radical Biology and Medicine, 73, 84-94. doi:10.1016/j.freeradbiomed.2014.04.026 Hüser, J., Rechenmacher, C. E., & Blatter, L. A. (1998). Imaging the permeability pore transition in single mitochondria. Biophysical Journal, 74(4), 2129-2137. doi:10.1016/S0006-3495(98)77920-2 Karlsson, H. L., Gustafsson, J., Cronholm, P., & Möller, L. (2009). 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A., & Robinson, J. P. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. The Journal of Biological Chemistry, 278(10), 8516-8525. doi:M210432200 Mathews, C. K., Holde, K. E. van, Appling, D. R., & Anthony-Cahill, S. J. (2013). Biochemistry (4th ed.). Toronto: Pearson. Mei, Y., Thompson, M. D., Cohen, R. A., & Tong, X. (2013). Endoplasmic reticulum stress and related pathological processes. Journal of Pharmacological & Biomedical Analysis, 1(2), 1000107-1000107. Miccadei, S., & Floridi, A. (1993). Sites of inhibition of mitochondrial electron transport by cadmium. Elsevier Scientific Publishers Ireland Ltd., 89, 159-167.Xu, X. M., & Møller, S. G. (2010). ROS removal by DJ-1: Arabidopsis as a new model to understand Parkinson's Disease. Plant signaling & behavior, 5(8), 1034–1036. doi:10.4161/psb.5.8.12298 Nicolson, G. L. (2014). Mitochondrial dysfunction and chronic disease: Treatment with natural supplements. Integrative Medicine (Encinitas, Calif.), 13(4), 35-43. Nicotera, P., Leist, M., & Ferrando-May, E. (1998). Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicology Letters, 102-103, 139-142. doi:<a href="https://doi.org/10.1016/S0378-4274(98)00298-7" style="color:blue; text-decoration:underline" target="_blank">https://doi.org/10.1016/S0378-4274(98)00298-7</a> Orrenius, S., Gogvadze, V., & Zhivotovsky, B. (2015). Calcium and mitochondria in the regulation of cell death. Biochemical and Biophysical Research Communications, 460(1), 72-81. doi:10.1016/j.bbrc.2015.01.137 Owen, J. B., & Butterfield, D. A. (2010). Measurement of oxidized/reduced glutathione ratio. Methods in Molecular Biology (Clifton, N.J.), 648, 269-277. doi:10.1007/978-1-60761-756-3_18 [doi] Pan, Y., Leifer, A., Ruau, D., Neuss, S., Bonrnemann, J., Schmid, G., . . . Jahnen-Dechent, W. (2009). Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(8), 2067-2076. doi:10.1002/smll.200900466 Pourahmad, J., Ghashang, M., Ettehadi, H. A., & Ghalandari, R. (2006). A search for cellular and molecular mechanisms involved in depleted uranium (DU) toxicity. Environmental Toxicology, 21(4), 349-354. doi:10.1002/tox.20196 Pozzan, T., & Rudolf, R. (2009). Measurements of mitochondrial calcium in vivo. Biochimica Et Biophysica Acta (BBA) - Bioenergetics, 1787(11), 1317-1323. doi:<a href="https://doi.org/10.1016/j.bbabio.2008.11.012" style="color:blue; text-decoration:underline" target="_blank">https://doi.org/10.1016/j.bbabio.2008.11.012</a> Roos, D., Seeger, R., Puntel, R., & Vargas Barbosa, N. (2012). Role of calcium and mitochondria in MeHg-mediated cytotoxicity. Journal of Biomedicine and Biotechnology, 2012, 1-15. doi:10.1155/2012/248764 Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology, 81(7), 495-504. doi:10.1007/s00204-006-0173-2 Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochimica Et Biophysica Acta - General Subjects, 1820(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015 Shaki, F., Hosseini, M., Ghazi-Khansari, M., & Pourahmad, J. (2013). Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria. Metallomics, 5(6), 736-744. doi:10.1039/c3mt00019b Turrens, J. F. (2003). Mitochondrial formation of reactive oxygen species. The Journal of Physiology, 552(Pt 2), 335-344. doi:jphysiol.2003.049478 [pii] Valko, M., Morris, H., & Cronin, M. T. (2005). 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2023-07-18T13:57:48

Impairment, Learning and memory

Individual

Learning can be defined as the process by which new information is acquired to establish knowledge by systematic study or by trial and error (Ono, 2009). Two types of learning are considered in neurobehavioral studies: a) associative learning and b) non-associative learning. Associative learning is based on making associations between different events. In associative learning, a subject learns the relationship among two different stimuli or between the stimulus and the subject’s behaviour. On the other hand, non-associative learning can be defined as an alteration in the behavioural response that occurs over time in response to a single type of stimulus. Habituation and sensitization are some examples of non-associative learning. The memory formation requires acquisition, retention and retrieval of information in the brain, which is characterised by the non-conscious recall of information (Ono, 2009). There are three main categories of memory, including sensory memory, short-term or working memory (up to a few hours) and long-term memory (up to several days or even much longer). Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems constituting functionally integrated neural networks (D’Hooge and DeDeyn, 2001). Among the many brain areas engaged in the acquisition of, or retrieval of, a learned event, the hippocampal-based memory systems have received the most study. For example, the hippocampus has been shown to be critical for spatial-temporal memory, visio-spatial memory, verbal and narrative memory, and episodic and autobiographical memory (Burgess et al., 2000; Vorhees and Williams, 2014). However, there is substantial evidence that fundamental learning and memory functions are not mediated by the hippocampus alone but require a network that includes, in addition to the hippocampus, anterior thalamic nuclei, mammillary bodies cortex, cerebellum and basal ganglia (Aggleton and Brown, 1999; Doya, 2000; Mitchell et al., 2002, Toscano and Guilarte, 2005; Gilbert et al., 2006, 2016). Thus, damage to variety of brain structures can potentially lead to impairment of learning and memory. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990).While the prefrontal cortex and frontostriatal neuronal circuits have been identified as the primary sites of higher-order cognition in vertebrates, invertebrates utilize paired mushroom bodies, shown to contain ~300,000 neurons in honey bees (Menzel, 2012; Puig et al., 2014). For the purposes of this KE (AO), impaired learning and memory is defined as an organism’s inability to establish new associative or non-associative relationships, or sensory, short-term or long-term memories which can be measured using different behavioural tests described below.

In laboratory animals: in rodents, a variety of tests of learning and memory have been used to probe the integrity of hippocampal function. These include tests of spatial learning like the radial arm maze (RAM), the Barnes maze, Hebb-Williams maze, passive avoidance and Spontaneous alternation and most commonly, the Morris water maze (MWM). Test of novelty such as novel object recognition, and fear based context learning are also sensitive to hippocampal disruption. Finally, trace fear conditioning which incorporates a temporal component upon traditional amygdala-based fear learning engages the hippocampus. A brief description of these tasks follows. 1) RAM, Barnes, MWM, Hebb-Williams maze are examples of spatial tasks, animals are required to learn the location of a food reward (RAM); an escape hole to enter a preferred dark tunnel from a brightly lit open field area (Barnes maze), or a hidden platform submerged below the surface of the water in a large tank of water (MWM) (Vorhees and Williams, 2014). The Hebb-Williams maze measures an animal’s problem solving abilities by providing no spatial cues to find the target (Pritchett & Mulder, 2004). 2) Novel Object recognition. This is a simpler task that can be used to probe recognition memory. Two objects are presented to animal in an open field on trial 1, and these are explored. On trial 2, one object is replaced with a novel object and time spent interacting with the novel object is taken evidence of memory retention – I have seen one of these objects before, but not this one (Cohen and Stackman, 2015). 3) Contextual Fear conditioning is a hippocampal based learning task in which animals are placed in a novel environment and allowed to explore for several minutes before delivery of an aversive stimulus, typically a mild foot shock. Upon reintroduction to this same environment in the future (typically 24-48 hours after original training), animals will limit their exploration, the context of this chamber being associated with an aversive event. The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009). 4) Trace fear conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, a light or a tone) and an aversive stimulus (US, a footshock). The unconditioned response (CR) that is elicited upon delivery of the footshock US is freezing behavior. With repetition of CS/US delivery, the previously neutral stimulus comes to elicit the freezing response. This type of learning is dependent on the amygdala, a brain region associated with, but distinct from the hippocampus. Introducing a brief delay between presentation of the neutral CS and the aversive US, a trace period, requires the engagement of the amygdala and the hippocampus (Shors et al., 2001). 5) Operant Responding. Performance on operant responding reflects the cortex’ ability to organize processes (Rabin et al., 2002).  In humans:  A variety of standardized learning and memory tests have been developed for human neuropsychological testing, including children (Rohlman et al., 2008). These include episodic autobiographical memory, perceptual motor tests, short and  long term memory tests, working memory tasks, word pair recognition memory; object location recognition memory. Some have been incorporated in general tests of intelligence (IQ) such as the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler. Modifications have been made and norms developed for incorporating of tests of learning and memory in children. Examples of some of these tests include: 1) Rey Osterieth Complex Figure test (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006). 2) Children’s Auditory Verbal Learning Test (CAVLT) is a free recall of presented word lists that yields measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak 1994; Talley, 1986). 3) Continuous Visual Memory Test (CVMT) measures visual learning and memory. It is a free recall of presented pictures/objects rather than words but that yields similar measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak, 1984; 1994). 4) Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986). 5) Autobiographical memory (AM) is the recollection of specific personal events in a multifaceted higher order cognitive process. It includes episodic memory- remembering of past events specific in time and place, in contrast to semantic autobiographical memory is the recollection of personal facts, traits, and general knowledge. Episodic AM is associated with greater activation of the hippocampus and a later and more gradual developmental trajectory. Absence of episodic memory in early life (infantile amnesia) is thought to reflect immature hippocampal function (Herold et al., 2015; Fivush, 2011). 6) Staged Autobiographical Memory Task. In this version of the AM test, children participate in a staged event involving a tour of the hospital, perform a series of tasks (counting footprints in the hall, identifying objects in wall display, buy lunch, watched a video). It is designed to contain unique event happenings, place, time, visual/sensory/perceptual details. Four to five months later, interviews are conducted using Children’s Autobiographical Interview and scored according to standardized scheme (Willoughby et al., 2014). 7) Attentional set-shifting (ATSET) task. Measures the ability to relearn cues over various schedules of reinforcement (Heisler et al., 2015). 8. Comprehensive developmental inventory for infants and toddlers (CDIIT).  The CDIIT was designed and standardized in 1996, and it measures the global, cognitive, language, motor, gross motor, fine motor, social, self-help and behavioral developmental status of children from 3 to 71 months old (Wang et al., 1998). In Honey Bees: For over 50 years an assay for evaluating olfactory conditioning of the proboscis extension reflex (PER) has been used as a reliable method for evaluating appetitive learning and memory in honey bees (Guirfa and Sandoz, 2012; LaLone et al., 2017). These experiments pair a conditioned stimulus (e.g., an odor) with an unconditioned stimulus (e.g., sucrose) provided immediately afterward, which elicits the proboscis extension (Menzel, 2012). After conditioning, the odor alone will lead to the conditioned PER. This methodology has aided in the elucidation of five types of olfactory memory phases in honey bee, which include early short-term memory, late short-term memory, mid-term memory, early long-term memory, and late long-term memory (Guirfa and Sandoz, 2012). These phases are dependent on the type of conditioned stimulus, the intensity of the unconditioned stimulus, the number of conditioning trials, and the time between trials. Where formation of short-term memory occurs minutes after conditioning and decays within minutes, memory consolidation or stabilization of a memory trace after initial acquisition leads to mid-term memory, which lasts 1 d and is characterized by activity of the cAMP-dependent PKA (Guirfa and Sandoz, 2012). Multiple conditioning trials increase the duration of the memory after learning and coincide with increased Ca2+-calmodulin-dependent PKC activity (Guirfa and Sandoz, 2012). Early long-term memory, where a conditioned response can be evoked days to weeks after conditioning requires translation of existing mRNA, whereas late long-term memory requires de novo gene transcription and can last for weeks (Guirfa andSandoz, 2012)."

Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans. Recently, larval zebrafish has also been suggested as a model for the study of learning and memory (Roberts et al., 2013). Life stage applicability: This key event is applicable to various life stages such as during brain development and maturity (Hladik & Tapio, 2016).  Sex applicability: This key event is not sex specific (Cekanaviciute et al., 2018), although sex-dependent cognitive outcomes have been recently ; Parihar et al., 2020).  Evidence for perturbation by a prototypic stressor: Current literature provides ample evidence of impaired learning and memory being induced by ionizing radiation (Cekanaviciute et al., 2018; Hladik & Tapio, 2016).

High Mixed

High

During brain development

High

Adult, reproductively mature

High High High High High High

Aggleton JP, Brown MW. (1999) Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci. 22: 425-489. Alexander RD (1990) Epigenetic rules and Darwinian algorithms: The adaptive study of learning and development. Ethology and Sociobiology 11:241-303. Bellinger DC (2012) A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Perspect 120:501-507. Burgess N (2002) The hippocampus, space, and viewpoints in episodic memory. Q J Exp Psychol A 55:1057-1080. Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176. Cekanaviciute, E., S. Rosi and S. Costes. (2018), "Central Nervous System Responses to Simulated Galactic Cosmic Rays", International Journal of Molecular Sciences, Vol. 19/11, Multidisciplinary Digital Publishing Institute (MDPI) AG, Basel,  https://doi.org/10.3390/ijms19113669.  Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176. Curzon P, Rustay NR, Browman KE. Cued and Contextual Fear Conditioning for Rodents. In: Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2009. D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60-90. Doya K. (2000) Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr Opin Neurobiol. 10: 732-739. Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41-50. Fivush R. 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Neuropsychology, Autobiographical Memory, and Hippocampal Volume in “Younger” and “Older” Patients with Chronic Schizophrenia. Front. Psychiatry, 6: 53. Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research/Reviews in Mutation Research, Vol. 770, Elsevier B. b., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.003.  Heisler, J. M. et al. (2015), "The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice", Journal of Visualized Experiments, 96, JoVe, Cambridge, https://doi.org/10.3791/51944. Heisler, J. M. et al. (2015), "The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice", Journal of Visualized Experiments, 96, JoVe, Cambridge, https://doi.org/10.3791/51944.  LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. 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(2002) Spatial working memory and the brainstem cholinergic innervation to the anterior thalamus. J Neurosci. 22: 1922-1928. OECD. 2007. OECD guidelines for the testing of chemicals/ section 4: Health effects. Test no. 426: Developmental neurotoxicity study. www.Oecd.Org/dataoecd/20/52/37622194.Pdf [accessed may 21, 2012]. OECD (2008) Nr 43 GUIDANCE DOCUMENT ON MAMMALIAN REPRODUCTIVE TOXICITY TESTING AND ASSESSMENT. ENV/JM/MONO(2008)16 Ono T. (2009) Learning and Memory. Encyclopedia of neuroscience. M D. Binder, N. Hirokawa and U. Windhorst (Eds). Springer-Verlag GmbH Berlin Heidelberg. pp 2129-2137. Parihar, V. K. et al. (2020), "Sex-Specific Cognitive Deficits Following Space Radiation Exposure", Frontiers in Behavioral Neuroscience, Vol. 14, https://doi.org/10.3389/fnbeh.2020.535885.  Pritchett, K. and G. Mulder. (2004), "Hebb-Williams mazes.", Contemporary topics in laboratory animal science, Vol. 43/5, http://www.ncbi.nlm.nih.gov/pubmed/15461441.  Puig, M.V., Antzoulatos, E.G., Miller, E.K., 2014. Prefrontal dopamine in associative learning and memory. Neuroscience 282, 217–229. Rabin, B. M. et al. (2002), "Effects of Exposure to 56Fe Particles or Protons on Fixed-ratio Operant Responding in Rats", Journal of Radiation Research, Vol. 43/S, https://doi.org/10.1269/jrr.43.S225.  Roberts AC, Bill BR, Glanzman DL. (2013) Learning and memory in zebrafish larvae. Front Neural Circuits 7: 126. Rohlman DS, Lucchini R, Anger WK, Bellinger DC, van Thriel C. (2008) Neurobehavioral testing in human risk assessment. Neurotoxicology. 29: 556-567. Shin, MS, Park, SY, Park, SR, Oeol, SH and Kwon, JS. (2006). Clinical and empirical applications of the Rey-Osterieth complex figure test. Nature Protocols, 1: 892-899. 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2023-06-26T12:44:45

N/A, Neurodegeneration

Tissue

The term neurodegeneration is a combination of two words - "neuro," referring to nerve cells and "degeneration," referring to progressive damage. The term "neurodegeneration" can be applied to several conditions that result in the loss of nerve structure and function, and neuronal loss by necrosis and/or apoptosis Neurodegeneration is a key aspect of a large number of diseases that come under the umbrella of “neurodegenerative diseases" including Huntington's, Alzheimer’s and Parkinson’s disease. All of these conditions lead to progressive brain damage and neurodegeneration. Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions, with gross atrophy of the affected regions; symptoms include memory loss. Parkinson's disease (PD) results from the death of dopaminergic neurons in the midbrain substantia nigra pars compacta; symptoms include bradykinesia, rigidity, and resting tremor. Several observations suggest correlative links between environmental exposure and neurodegenerative diseases, but only few suggest causative links: Only an extremely small proportion (less than 5%) of neurodegenerative diseases are caused by genetic mutations (Narayan and Dragounov, 2017). The remainders are thought to be caused by the following: ·      A build up of toxic proteins in the brain (Evin et al., 2006) ·      A loss of mitochondrial function that leads to the oxidative stress and creation of neurotoxic molecules that trigger cell death (apoptotic, necrotic or autophagy) (Cobley et al., 2018) ·      Changes in the levels and activities of neurotrophic factors (Kazim and Iqbal, 2016; Machado et al., 2016; Rodriguez et al., 2014) ·      Variations in the activity of neural networks (Greicius and Kimmel, 2012) Protein aggregation: the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognised, but a causal relationship has not been unequivocally established (Lansbury et al., 2006; Kumar et al., 2016). The dynamic nature of protein aggregation mean that, despite progress in understanding its mechanisms, its relationship to disease is difficult to determine in the laboratory. Nevertheless, drug candidates that inhibit aggregation are now being tested in the clinic. These have the potential to slow the progression of Alzheimer's disease, Parkinson's disease and related disorders and could, if administered pre-symptomatically, drastically reduce the incidence of these diseases. Loss of mitochondrial function: many lines of evidence suggest that mitochondria have a central role in neurodegenerative diseases (Lin and Beal, 2006). Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Dysfunction of mitochondria induces oxidative stress, production of free radicals, calcium overload, and mutations in mitochondrial DNA that contribute to neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease- specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise. Decreased level of neurotrophic factors: decreased levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington's disease, Alzheimer disease and Parkinson disease (Zuccato and Cattaneo, 2009). These studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic the aforementioned human diseases, with a view to ultimately influencing the clinical treatment of these conditions. Therefore BDNF treatment is being considered as a beneficial and feasible therapeutic approach in the clinic. Variations in the activity of neural networks: Patients with various neurodegenerative disorders show remarkable fluctuations in neurological functions, even during the same day (Palop et al., 2006). These fluctuations cannot be caused by sudden loss or gain of nerve cells. Instead, it is likely that they reflect variations in the activity of neural networks and, perhaps, chronic intoxication by abnormal proteins that the brain is only temporarily able to overcome. Neurodegeneration in relation to COVID19 SARS-CoV-2 patients present elevated plasma levels of neurofilament light chain protein (NfL), which is a well-known biochemical indicator of neuronal injury (Kanberg et al., 2020). Postmortem brain autopsies demonstrate virus invasion to different brain regions, including the hypothalamus and olfactory bulb, accompanied by neural death and demyelination (Archie and Cucullo 2020; Heneka et al. 2020). Autopsy results of patients with SARS showed ischemic neuronal damage and demyelination; viral RNA was detected in brain tissue, particularly accumulating in and around the hippocampus (Gu et al. 2005). Brain magnetic resonance imaging (MRI) investigations in SARS-CoV-2 patients show multifocal hyperintense white matter lesions and cortical signal abnormalities (particularly in the medial temporal lobe) on fluid-attenuated inversion recovery (FLAIR), along with intracerebral hemorrhagic and microhemorrhagic lesions, and leptomeningeal enhancement (Kandemirli et al. 2020; Kremer et al. 2020; Mohammadi et al., 2020). Moreover, eight COVID-19 patients with signs of encephalopathy had anti–SARS-CoV-2 antibodies in their CSF, and 4 patients had CSF positive for 14-3-3-protein suggesting ongoing neurodegeneration (Alexopoulos et al. 2020).

The assays for measurements of necrotic or apoptotic cell death are described in the Key Event: Cell injury/Cell death Recent neuropathological studies have shown that Fluoro-Jade, an anionic fluorescent dye, is a good marker of degenerating neurons. Fluoro-Jade and Fluoro-Jade B were found to stain all degenerating neurons, regardless of specific insult or mechanism of cell death (Schmued et al., 2005). More recently, Fluoro-Jade C was shown to be highly resistant to fading and compatible with virtually all histological processing and staining protocols (Schmued et al., 2005). In addition, Fluoro-Jade C is a good tool for detecting acutely and chronically degenerating neurons (Ehara and Ueda, 2009).

The necrotic and apoptotic cell death pathways are quite well conserved throughout taxa (Blackstone and Green, 1999, Aravind et al., 2001). It has been widely suggested that apoptosis is also conserved in metazoans, although despite conservation of Bcl-2 proteins, APAF-1, and caspases there is no biochemical evidence of the existence of the mitochondrial pathway in either C. elegans or Drosophila apoptosis (Baum et al., 2007; Blackstone and Green, 1999).

UBERON:0000955

UBERON brain

High Mixed

High

During brain development, adulthood and aging

High High Moderate

Aravind, L., Dixit, V. M., and Koonin, E. V. (2001). Apoptotic Molecular Machinery: Vastly Increased Complexity in Vertebrates Revealed by Genome Comparisons. Science 291, 1279-1284. Baum, J. S., Arama, E., Steller, H., and McCall, K. (2007). The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis. Cell Death Differ 14, 1508-1517. Blackstone, N. W., and Green, D. R. (1999). The evolution of a mechanism of cell suicide. Bioessays 21, 84-88. Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15: 490-503 Ehara A, Ueda S. 2009. Application of Fluoro-Jade C in acute and chronic neurodegeneration models: utilities and staining differences. Acta histochemica et cytochemica 42(6): 171-179. Evin G, Sernee MF, Masters CL (2006) Inhibition of gamma-secretase as a therapeutic intervention for Alzheimer's disease: prospects, limitations and strategies. CNS Drugs 20: 351-72 Greicius MD, Kimmel DL (2012) Neuroimaging insights into network-based neurodegeneration. Curr Opin Neurol 25: 727-34 Kazim SF, Iqbal K (2016) Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease. Mol Neurodegener 11: 50 Kumar V, Sami N, Kashav T, Islam A, Ahmad F, Hassan MI (2016) Protein aggregation and neurodegenerative diseases: From theory to therapy. Eur J Med Chem 124: 1105-1120 Lansbury1 PT & Lashuel HA (2006) A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443, 774-779. Lin1 MT & Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795 Machado V, Zoller T, Attaai A, Spittau B (2016) Microglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson's Disease-Lessons from Transgenic Mice. Int J Mol Sci 17 Narayan P, Dragunow M (2017) Alzheimer's Disease and Histone Code Alterations. Adv Exp Med Biol 978: 321-336 Palop JJ, Chin1 J & Mucke L, Review Article A network dysfunction perspective on neurodegenerative diseases. 2006, Nature 443, 768-773 Rodrigues TM, Jeronimo-Santos A, Outeiro TF, Sebastiao AM, Diogenes MJ (2014) Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson's disease. Drugs Aging 31: 239-61 Schmued LC, Stowers CC, Scallet AC, Xu L. 2005. Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res 1035(1): 24-31. Zuccato C & Cattaneo E, Brain-derived neurotrophic factor in neurodegenerative diseases.2009, Nature Reviews Neurology 5, 311-3 COVID19-related references relevant to KE Neurodegeneration: Alexopoulos et al. Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: Studies in 8 stuporous and comatose patients. Neurol Neuroimmunol Neuroinflamm. 2020 Sep 25;7(6):e893. Archie SR, Cucullo L. Cerebrovascular and neurological dysfunction under the threat of COVID-19: is there a comorbid role for smoking and vaping? Int J Mol Sci. 2020 21(11):3916 12. Gu J et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–424. Heneka MT, et al. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020 12(1):1–3. Kandemirli SG, et al. Brain MRI findings in patients in the intensive care unit with COVID-19 infection. Radiology. 2020 Oct;297(1):E232-E235. Kanberg N, et al. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology. 2020 Sep 22;95(12):e1754-e1759. Kremer S, et al. Brain MRI findings in severe COVID-19: a retrospective observational study. Radiology. 2020 Nov;297(2):E242-E251. Mohammadi S. et al. Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms. Mol Neurobiol. 2020 Dec;57(12):5263-5275. AOPWiki 2016-11-29T18:41:24

2021-02-23T05:07:07

Increased, Reactive oxygen species

Cellular

Biological State: increased reactive oxygen species (ROS) Biological compartment: an entire cell -- may be cytosolic, may also enter organelles. Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017).  However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015).

Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies. Yuan, Yan, et al., (2013) described ROS monitoring by using H2-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H2-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm. Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013). Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.

ROS is a normal constituent found in all organisms.

High Unspecific

High

All life stages

High

B.H. Park, S.M. Fikrig, E.M. Smithwick Infection and nitroblue tetrazolium reduction by neutrophils: a diagnostic aid Lancet, 2 (1968), pp. 532-534 Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313. Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85. Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659. Chattopadhyay, Sukumar, et al. "Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants." Toxicology letters 136.1 (2002): 65-76. Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81. Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304. Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75. Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen. Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier. Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. “p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 88 (April): 218–31. Yen, Cheng Chien, et al. "Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway." Archives of toxicology 85 (2011): 565-575. Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330. AOPWiki 2016-11-29T18:41:29

2023-07-26T14:34:09

Apoptosis

Cellular

Apoptosis, the process of programmed cell death, is characterized by distinct morphology with DNA fragmentation and energy dependency [Elmore, 2007]. Apoptosis, also called “physiological cell death”, is involved in cell turnover, physiological involution, and atrophy of various tissues and organs [Kerr et al., 1972]. The formation of apoptotic bodies involves marked condensation of both nucleus and cytoplasm, nuclear fragmentation, and separation of protuberances [Kerr et al., 1972]. Apoptosis is characterized by DNA ladder and chromatin condensation. Several stimuli such as hypoxia, nucleotides deprivation, chemotherapeutical drugs, DNA damage, and mitotic spindle damage induce p53 activation, leading to p21 activation and cell cycle arrest [Pucci et al., 2000]. The SAHA or TSA treatment on neonatal human dermal fibroblasts (NHDFs) for 24 or 72 hrs inhibited proliferation of the NHDF cells [Glaser et al., 2003]. Considering that the acetylation of histone H4 was increased by the treatment of SAHA for 4 hrs, histone deacetylase inhibition may be involved in the inhibition of the cell proliferation [Glaser et al., 2003]. The impaired proliferation was observed in HDAC1-/- ES cells, which was rescued with the reintroduction of HDAC1 [Zupkovitz et al., 2010]. The present AOP focuses on the p21 pathway leading to apoptosis, however, alternative pathways such as NF-kappaB signaling pathways may be involved in the apoptosis of spermatocytes [Wang et al., 2017].

Apoptosis is characterized by many morphological and biochemical changes such as homogenous condensation of chromatin to one side or the periphery of the nuclei, membrane blebbing and formation of apoptotic bodies with fragmented nuclei, DNA fragmentation, enzymatic activation of pro-caspases, or phosphatidylserine translocation that can be measured using electron and cytochemical optical microscopy, proteomic and genomic methods, and spectroscopic techniques [Archana et al., 2013; Martinez et al., 2010; Taatjes et al., 2008; Yasuhara et al., 2003]. ・DNA fragmentation can be quantified with comet assay using electrophoresis, where the tail length, head size, tail intensity, and head intensity of the comet are measured [Yasuhara et al., 2003]. ・The apoptosis is detected with the expression alteration of procaspases 7 and 3 by Western blotting using antibodies [Parajuli et al., 2014]. ・The apoptosis is measured with down-regulation of anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, or cIAP1) [Parajuli et al., 2014]. ・Apoptotic nucleosomes are detected using Cell Death Detection ELISA kit, which was calculated as absorbance subtraction at 405 nm and 490 nm [Parajuli et al., 2014]. ・Cleavage of PARP is detected with Western blotting [Parajuli et al., 2014]. ・Caspase-3 and caspase-9 activity is measured with the enzyme-catalyzed release of p-nitroanilide (pNA) and quantified at 405 nm [Wu et al., 2016]. ・Apoptosis is measured with Annexin V-FITC probes, and the relative percentage of Annexin V-FITC-positive/PI-negative cells is analyzed by flow cytometry [Wu et al., 2016]. ・Apoptosis is detected with the Terminal dUTP Nick End-Labeling (TUNEL) method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks [Kressel and Groscurth, 1994]. ・For the detection of apoptosis, the testes are fixed in neutral buffered formalin and embedded in paraffin. Germ cell death is visualized in testis sections by Terminal dUTP Nick End-Labeling (TUNEL) staining method [Wade et al., 2008]. The incidence of TUNEL-positive cells is expressed as the number of positive cells per tubule examined for one entire testis section per animal [Wade et al., 2008]. <ul> <li>Apoptosis is detected with the Annexin V test</li> </ul>

・Apoptosis is induced in human prostate cancer cell lines (Homo sapiens) [Parajuli et al., 2014]. ・Apoptosis occurs in B6C3F1 mouse (Mus musculus) [Elmore, 2007]. ・Apoptosis occurs in Sprague-Dawley rat (Rattus norvegicus) [Elmore, 2007]. ・Apoptosis occurs in the nematode (Caenorhabditis elegans) [Elmore, 2007]. <ul> <li>Apoptosis occurs in breast cancer cells, human and mouse</li> </ul>

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Unspecific

High

Not Otherwise Specified

High High High High

Archana, M. et al. (2013), "Various methods available for detection of apoptotic cells", Indian J Cancer 50:274-283 Elmore, S. (2007), "Apoptosis: a review of programmed cell death", Toxicol Pathol 35:495-516 Glaser, K.B. et al. (2003), "Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines", Mol Cancer Ther 2:151-163 Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257 Kressel, M. and Groscurth, P. (1994), "Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA", Cell Tissue Res 278:549-556 Martinez, M.M. et al. (2010), "Detection of apoptosis: A review of conventioinal and novel techniques", Anal Methods 2:996-1004 Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313 Pucci, B. et al. (2000), "Cell cycle and apoptosis", Neoplasia 2:291-299 Taatjes, D.J. et al. (2008), "Morphological and cytochemical determination of cell death by apoptosis", Histochem Cell Biol 129:33-43 Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831 Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143 Wu, R. et al. (2016), "microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs", PLoS One 11:e0167052 Yasuhara, S. et al. (2003), "Comparison of comet assay, electron microscopy, and flow cytometry for detection of apoptosis", J Histochem Cytochem 51:873-885 Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181 AOPWiki 2017-02-07T13:21:50

2022-12-20T08:33:23

<upstream-id>a2ce2f28-4c51-4aba-96e6-bb9a95587a07</upstream-id> <downstream-id>7a549d0e-9fb7-48f5-be3d-856580754b48</downstream-id> Astrocytes are networked together by a series of gap junctions permitting to propagate Ca2+ waves through the linked network (Lobsiger and Cleveland 2007), and Ca2+-mediated intercellular communication is a mechanism by which astrocytes communicate with each other and modulate the activity of adjacent cells (Verderio et al., 2001). Metal mixture (MM) induced alteration in astrocyte morphology may influence [Ca2+]i (Barres et al., 1989); in contrast, an increase in [Ca2+]i may also play a key role in altering astrocyte cytoskeleton, affecting the glia-neuron interaction (Shelton et al., 2000). Inhibition of GFAP immunoreactivity by MM in developing brain appears to be caused by astrocyte apoptosis. In primary cultures of astrocytes, our data show that MM synergistically induced apoptosis (Rai and others 2010). This was manifested by the activation of MEK/ERK, followed by the activation of JNK pathways, which then enhanced intracellular Ca2+ levels and subsequently ROS generation.

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOPs "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release" and "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

We treated the astrocytes with a metal-mixture (MM) of arsenic, cadmium, and lead and observed that the MM triggered [Ca2+]i release (Rai and others 2010). The [Ca2+]i release reached its peak after 30 min of MM treatment. Similarly, MM triggered ROS generation, and the ROS generation reached its peak after 1 h of MM treatment. To investigate whether the [Ca2+]i release was ROS, ERK1/2, or JNK1/2 –dependent, we incubated the MM-treated astrocytes with an antioxidant (a-tocopherol, 200 lg/ml), PD98059 (10lM), or SP600125 (10lM). a-Tocopherol itself was nontoxic. We observed that PD98059 (10lM) or SP600125 (10lM) suppressed [Ca2+]i release, but a-tocopherol (200 lg/ml) did not. This suggested that [Ca2+]i release in MM-treated astrocytes was ERK1/2 and JNK1/2 dependent (Rai and others 2010). Yael and Breitbart (2015) demonstrated for the first time that mouse sperm ERK1/2 is activated upon ZP addition, and that ERK1/2 mediates the elevation of intracellular Ca2+ in the sperm cell prior to the occurrence of the acrosome reaction. The fact that the acrosome reaction, induced by the Ca2+-ionophore A23187, was not inhibited by U0126 suggests that ERK1/2 mediates the acrosome reaction by activating Ca2+ transport into the cell. Direct determination of intracellular [Ca2+] revealed that Ca2+ influx induced by EGF or ZP was completely blocked by U0126. Thus, it has been established that the increase in ERK1/2 phosphorylation/activation in response to ZP or by activation of the EGF receptor (EGFR) by EGF, is a key event for intracellular Ca2+ elevation and the subsequent occurrence of the acrosome reaction (Jaldety et al., 2015). To examine the relationship between Ca2+ and Erk1/2 signaling, Levin and Borodinsky (2022) inhibited Mek1/2 with PD0325901 and found that this prevents the injury-induced increase in Ca2+ activity in cells lateral to the axial musculature across the entire 800 µm-wide region measured. This suggests that injury-induced Erk1/2 activation recruits Ca2+ activity to promote regeneration of the larval tail. Consistent with recruitment of Ca2+ activity across a wide region of tail, activated Erk1/2 is also present in at least the posterior 800 µm of stump (Levin et al., 2022). However, unlike Ca2+ activity, Erk1/2 signaling at 20 mpa is activated in a gradient. This could mean that even the lowest level of Erk1/2 signal measured in 800 µm of amputated tail is sufficient to induce the Ca2+ response, or that a signal is propagated anteriorly from the cells adjacent to the amputation where injury induces high Erk1/2 activation (Levin et al., 2022).

Exposures were conducted for 2 min, 5 min, 10 min, 30 min, 1 h, 2 h, and 24 h.  The [Ca2+]i release reached its peak after 30 min of MM treatment (Rai and others 2010).

The activity of many protein kinases is modulated by Ca2+ and/or Ca2+/calmodulin either directly (PKC, CaM kinase II) or indirectly (PKA via stimulation of adenylyl cyclase and phosphodiesterase by Ca2+/calmodulin) (Kern et al., 1995). Therefore, the effects of Ca2+ and protein kinases on cytoskeletal proteins and neurite initiation are likely to be mediated, at least in part, by changes in protein phosphorylation (Kern et al., 1995).

Moderate Female Moderate Mixed

Moderate

Birth to < 1 month

Moderate

1 to < 3 months

Moderate

Pregnancy

Moderate Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eabe94b8> AOPWiki 2023-06-20T16:26:37

2023-07-21T17:07:05

<upstream-id>7a549d0e-9fb7-48f5-be3d-856580754b48</upstream-id> <downstream-id>ed20656b-94b8-472c-894c-cd876800a9b1</downstream-id>

<div> This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June. </div>

It is well established that variations in cytosolic calcium concentration [Ca2+]c trigger key cellular functions, for example, contraction of myofilaments, secretion of hormones and neurotransmitters and modulation of metabolism (Berridge et al., 2003; Rizzuto and Pozzan 2006; Clapham 2007). Moreover, Ca2+ also has a major function in triggering mitotic division in numerous cell types (e.g., T lymphocytes and of oocytes) and, conversely, in the regulation of cell death (Giorgi et al., 2008). The notion that the cellular Ca2+ overload is highly toxic, causing massive activation of proteases and phospholipases was known to cell biologists since the late 1960s (Pinton et al., 2008).

<div> Calcium is a ubiquitous intracellular signal responsible for controlling numerous cellular processes including cell proliferation, differentiation, and survival/death (Clapham 2007). Studies have shown that Cd disrupts intracellular free calcium ([Ca2+]i) homeostasis, leading to apoptosis in a variety of cells, such as skin epidermal cells (Son et al., 2010), hepatic cells (Lemarie et al., 2004; Xie et al., 2010), lymphoblastoid cells (Lemarie et al., 2004), mesangial cells (Wang et al., 2008; Liu and Templeton 2008; Yang et al., 2009), renal tubular cells (Yeh et al., 2009; Wang et al., 2009), astrocytes (Yang et al., 2008), NIH 3T3 cells (Biagioli et al., 2008), thyroid cancer cells (Liu et al., 2007), and thymocytes (Shen et al., 2001). Baoshan et al. (2011) determined the role of calcium signaling in Cd-induced neuronal apoptosis.  PC12 and SH-SY5Y cells, respectively, were treated with 0–20 µM Cd for 24 h, or with 10 and 20 µM Cd for 0–24 h. Subsequently, [Ca2+]i was measured with a calcium indicator dye, Fluo-3/AM or Fluo-4/AM. We found that treatment with Cd (0–20 µM) resulted in a concentration-dependent increase of [Ca2+]i in PC12 cells. Cd also induced a time-dependent elevation of [Ca2+]i in the cells during the period of 24 h. Similarly, Cd markedly elicited high [Ca2+]i fluorescence intensity in a concentration- and time-dependent manner in SH-SY5Y cells by fluorescence microscopy. Furthermore, Cd-elevated [Ca2+]i level was consistent with decreased cell viability or increased apoptosis of PC12 and SH-SY5Y cells (Chen et al., 2008), suggesting that Cd-induced neuronal apoptosis might be associated with its induction of [Ca2+]i elevation (Baoshan et al., 2011). Yuan, Yan, et al. (2013) found that treatment with Cd (5, 10, 20 µM) resulted in a concentration-dependent increase of [Ca2+]i in cerebral cortical neurons. To verify the role of [Ca2+]i as a key second messenger, cells were pre-loaded with 10 µM BAPTA-AM for 30 min. Chelating intracellular Ca2+ with BAPTA-AM prevented the elevation of [Ca2+]i, demonstrating that the release of intracellular Ca2+ is essential for Cd-induced [Ca2+]i overloading. To explore other factors contributing to the calcium overload, we studied the effect of Cd on the activities of ATPases (Yuan et al., 2013). Treatment of cerebral cortical neurons with Cd resulted in a significant loss in the activities of ATPases (P<0.05 or P<0.01), which occurred in a dose-dependent manner. When exposed to 5, 10 and 20 µM of Cd for 12 h, the Na+/K+-ATPase activity decreased to 70.1%, 52.5% and 27.2% of the control value while the Ca2+/Mg+-ATPase activity decreased to 62.6%, 49.0% and 25.5% of the control value, respectively. To examine the role of the ER in Cd-induced elevation of [Ca2+]i, we incubated neurons with 2-APB, a blocker of the ER calcium channel (inositol-1, 4, 5-trisphosphate receptor, IP3R). We observed that the elevation of [Ca2+]i induced by Cd was suppressed by 2-APB after treatment with Cd for 12 h. Taken together, these results demonstrated that [Ca2+]i elevation induced by Cd in cerebral cortical neurons is linked to the release of calcium from the ER (Yuan et al., 2013). Next, to further determine the role of calcium in the regulation of Cd-induced apoptosis, cerebral cortical neurons were incubated with/without Cd (10 µM) in the absence or presence of BAPTA-AM (10 µM). Cd alone (10 µM) induced cell rounding and shrinkage, and BAPTA-AM itself did not alter cell shape. However, BAPTA-AM obviously blocked Cd-induced morphological changes. Furthermore, MTT assay results further demonstrated that BAPTA-AM in part can suppress Cd-induced loss of cell viability in Cd-exposed cerebral cortical neurons. These results suggest that Cd-induced neuronal apoptosis might be associated with its induction of [Ca2+]i elevation (Yuan et al., 2013). Independent evidence for the involvement of Ca2+ influx in the triggering of apoptosis has come from studies with specific Ca2+ channel blockers, which abrogate apoptosis in the regressing prostate following testosterone withdrawal (Martikainen and Isaacs 1990) and in pancreatic b-cells treated with serum from patients with type I diabetes (Juntti-Berggren et al., 1993). Other support for the involvement of Ca2+ in apoptosis comes from the observation that agents which directly mobilize Ca2+can trigger apoptosis in diverse cell types (McConkey and Orrenius 1997). Wyllie et al., (1984) demonstrated that Ca2+ ionophores cause endonuclease activation as well as many of the morphological changes that are typical of apoptosis in thymocytes. Calcium ionophores also trigger apoptosis in prostate tumor cells (Martikainen and Isaacs 1990). Other support for this echanism has come from studies with the endoplasmic reticular Ca2+-ATPase inhibitor thapsigargin, the product of the plant, Thapsa garganica, which can also trigger all of the morphological and biochemical events of apoptosis in thymocytes (Jiang et al., 1994) and some other cell types (Levick et al., 1995; Kaneko and Tsukamoto 1994; Choi et al., 1995). </div>

The duration and extent of Ca2+ influx may determine whether cells survive, die by apoptosis, or undergo necrotic lysis (Choi 1995). According to this paradigm, continuous, but  moderate increases in [Ca2+]i such as those produced by a sustained slow influx may cause apoptosis, whereas an exceedingly high influx rate would cause rapid cell lysis (Nicotera et al., 1998). For instance, collaborative work with Dr Stuart A. Lipton’s laboratory has shown that stimulation of cortical neurons with high concentrations of NMDA results in necrosis, whereas exposure to lower concentrations causes apoptosis (Bonfoco et al., 1995). Correspondingly, neuronal death in experimental stroke models is necrotic in the ischemic core, but delayed and apoptotic in the less severely compromised penumbra or border regions (Li et al., 1995; Charriaut-Marlangue et al., 1995). Further studies in our laboratories have shown that intracellular energy levels are rapidly dissipated in necrosis, but not in apoptosis (Cox et al., 1990; Matson et al., 1989). These results suggest that while initial events may be common to both types of cell death, certain metabolic conditions would be required to activate downstream controllers, which direct cells towards the organized execution of apoptosis (Leist and Nicotera 1997).

Moderate Unspecific

Moderate

All life stages

Moderate Moderate Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eaca8408> AOPWiki 2023-07-18T14:53:24

2023-07-26T14:20:20

<upstream-id>7a549d0e-9fb7-48f5-be3d-856580754b48</upstream-id> <downstream-id>6a8c1421-886d-49d9-8cd3-9814f656b76c</downstream-id> One of the better characterized apoptotic cascade pathways has mitochondrial dysfunction as its initiator. Mitochondrial dysfunction initiated by the opening of the mitochondrial transition pore leads to mitochondrial depolarization, release of cytochrome C, activation of a variety of caspases and cleavage of downstream death effector proteins, and  ultimately results in apoptotic cell death. While a variety of stimuli can trigger opening of the mitochondrial transition pore and cause apoptosis, a sustained intracellular increase in Ca2+ is one of the better-known triggers (Mattson 2000).

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

Intracellular calcium overload may be related to the mitochondrial dysfunction (Yuan et al., 2013). Mitochondria are vital organelles for cellular metabolism and bioenergetics, but they are also key regulators of cell death (Fantin and Leder 2006). Since mitochondria are the major site of ATP production and mitochondrial ΔΨ is the driving force of ATP synthesis, a breakdown in the mitochondrial ΔΨ could lead to a fall in the ATP levels (Chakraborti et al., 1999). The resulting reduction in cellular ATP levels can disrupt ionic homeostasis which can cause an increase in [Ca2+]i and subsequent cellular apoptosis/necrosis (Grammatopoulos et al., 2004). Notably, in many (if not all) paradigms of apoptosis, ΔΨm represents the point of no return in the cascade of events that ultimately leads to cell death (Kroemer et al., 2007). The effector phase of apoptosis involves increased mitochondrial Ca2+ and oxyradical levels, the formation of permeability transition pores (PTP) in the mitochondrial membrane, and release of cytochrome c into the cytosol (Mattson 2000). The increase of free radicals and Ca2+ levels associated to Cd exposure may induce mitochondrial disruption (Fern et al., 1996). Intracellular calcium homeostasis is very important in maintaining the normal function of the cell, in that variations in the concentration of calcium in cells can determine cell survival or death. For example, a high [Ca2+]i can cause disruption of mitochondrial Ca2+ equilibrium, which results in reactive oxygen species (ROS) formation due to the stimulation of electron flux along the electron transport chain (ETC) (Chacon and Acosta 1991). Under oxidative stress, mitochondrial Ca2+ accumulation can switch from a physiologically beneficial process to a cell death signal (Ermak and Davies 2002).

Yuan, Yan, et al. 2013 found that BAPTA-AM significantly blocked disruption of Δψm in cells exposed to Cd (5, 10 and 20 µM) for 12 h. Furthermore, cleavage of caspase-9, caspase-3 and PARP were significantly attenuated by BAPTA-AM, which was in agreement with thier observation that BAPTA-AM profoundly prevented Cd-induced apoptosis and cell death of cerebral cortical neurons. However, increased Bax and decreased Bcl-2 levels were not blocked by BAPTA-AM . These data suggest that calcium-mediated mitochondria-caspase b is involved in Cd-induced apoptosis. Moreover, thier results collectively suggested that Cd-induced apoptosis of cerebral cortical neurons occurs through a calcium-mitochondria signaling pathway (Yuan et al., 2013). Yuan, Yan, et al. 2013 also noted that reduced expression of Bcl-2 increases the expression of Bax, which results in an overload of Ca2+ in the mitochondria and promotes the opening of permeability transition pores causing mitochondria to swell, with their outer membranes collapsing and exiting into the cytoplasm, which would consequently trigger apoptosis.

Moderate Unspecific Moderate Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ead4e1a0> AOPWiki 2023-06-20T16:41:23

2023-07-25T16:12:37

<upstream-id>6a8c1421-886d-49d9-8cd3-9814f656b76c</upstream-id> <downstream-id>44afdb8a-64b8-4b89-9b7b-7789d759692c</downstream-id> <div> Mitochondria play a role in stress responses and can produce ROS when damaged. Mitochondria are indeed a major source of ROS (Yuan et al., 2013). ROS production is related to the level of ETC (Fleury et al., 2002); it is elevated when electron transport is reduced, which occurs in pathological situations (Wallace 2005). </div>

<div> A phenotype that is commonly associated with mitochondrial dysfunction, and in fact with many age-related diseases, is the accumulation of damage attributable to the buildup of reactive oxygen species (Leadsham et al., 2013). Indeed, a vicious cycle of decline in which ROS arising from the mitochondrial electron transport chain (ETC) leads to the damage to mitochondrial DNA and a resultant increase in radical production provides the cornerstone of the much scrutinized free radical theory of aging (Harman 1956). However, ROS also serve as important signaling molecules that can promote longevity in C. elegans (Schulz et al., 2007) and also in yeast (Mesquita et al., 2010). Alterations in mitochondrial physiology could be involved in programmed cell death (PCD). First, reactive oxygen species (ROS) may participate as effector molecules in PCD (Hockenbery et al., 1993; Kane et al., 1993; Sandstrom et al., 1994). </div>

<div> Lopez et al. (2006) showed that in cortical neurons, cadmium exposure induced cellular death, which was, in part, reversed by vitamin C, an antioxidant agent.  The apoptosis produced by cadmium was reversed by vitamin C while the necrosis was not affected by this antioxidant molecule. It also appears that in the apoptotic mechanism mediated by cadmium, but not in the necrotic mechanisms, oxidative stress could be implicated. The ability of cadmium to induce oxidative stress in cortical neurons is aided by the induction of ROS by this cation. Cortical neurons treated with cadmium ions at concentrations between 1 and 100 μM, in either the absence or in the presence of serum in the treatment medium, generated ROS. The induction of ROS in these cells type could be mediated by mitochondria alterations because cadmium produces a breakdown of the mitochondrial membrane potential. The decreases in ATP levels and in the mitochondria membrane potential began at 10 and 50 μM cadmium ion, respectively, while the ROS formation was detected at lower doses (100 nM or 1 μM). These results likely indicate that ROS formation occurs or it is detectable before the toxic events on mitochondrial function that lead to the breakdown in mitochondrial potentials. Zamzami et al. (1995) concluded that at a final level, the shrinkage of ΔΨmlowHE+ cells is selectively inhibited by substances that suppress mitochondrial ROS generation (rotenone, ruthenium red), as well as by antioxidants such as the vitamin E derivative trolox, alone or incombination with L-ascorbate, or the radical scavenger N-t-butyl-alpha-phenylnitrone. This observation confirms that ROS are PCD effector molecules. In synthesis, these data indicate that ΔΨm reduction and enhanced mitochondrial ROS generation indeed represent two clearly distinct phases of the preapoptotic process. Only after ΔΨm has dropped are ROS generated and do they participate in the perturbation of mitochondrial membranes, as well as in later manifestations of PCD such as cell shrinkage. Zamazim et al. (1995) went on to state that reduction in ΔΨm and subsequent KOS hyperproduction are observed in several in vitro models of physiological PCD, i.e., models in which nontoxic agents were used to induce PCD in susceptible target cells: TNF-a in U937 cells and anti-IgM in WEHI 231 pre-B cells, as well as CD3 cross-linking in T cell hybridomas. Ceramide, a second messenger involved in the mediation of some PCD types (Obeid et al., 1993; Haimovitz-Friedman et al., 1994), also causes these effects. In all of these systems, alterations in mitochondrial  function precede DNA fragmentation and nuclear DNA loss. Thus, it appears that mitochondrial derangement is a constant feature of PCD occurring independently of the PCD-inducing stimulus. Zhang et al. (2004) reported that Mn2+ exposure inhibited the complexes I–IV compared to the control. The inhibition of the respiratory activity by Mn2+ is accompanied by a substantial increase of ROS production rate. They went on to report that NAC, GSH and vitamin C are effective in the prevention of Mn2+-induced ROS production and decreases of complexes I–IV activity in isolated mitochondria. Preventive effects of NAC and GSH reveal that cellular GSH are crucial for protection against Mn2+-induced toxicity. </div>

Moderate Unspecific Moderate Moderate Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eade0ca8> AOPWiki 2023-07-18T13:38:46

2023-07-25T16:22:04

<upstream-id>44afdb8a-64b8-4b89-9b7b-7789d759692c</upstream-id> <downstream-id>ed20656b-94b8-472c-894c-cd876800a9b1</downstream-id> <div> <div> ROS generation in normal cells, including neurons, occurs within homeostatic control. When ROS levels exceed the antioxidant capacity of a cell, a deleterious condition known as oxidative stress occurs (Klein and Ackerman 2003). Unchecked, excessive ROS can lead to the destruction of cellular components including lipids, protein, and DNA, and ultimately cell death via apoptosis or necrosis (Kannan and Jain 2000). </div> </div>

<div> <div> This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June. </div> </div>

<div> <div> Reactive oxygen species (ROS) can be derived from exogenous sources or produced in vivo; these include the superoxide anion (O 2��), the hydroxyl radical (�OH), and hydrogen  peroxide (H 2O2). ROS at low levels participate in cell signaling while higher ROS concentrations are deleterious due to the oxidation of proteins, lipids, and DNA. Additionally,  persistent ROS production compromises the cellular antioxidant defense systems and results in oxidative stress and apoptosis (337). ROS can initiate apoptosis via the  mitochondrial and death receptor pathways. In the former, ROS have been shown to induce loss of the ��m, release of mitochondrial pro-apoptotic proteins, and activation of caspase 3 (49). ROS signaling has been shown to mediate cytokine-induced apoptosis (Okouchi et al., 2007). TNF� is a pro-inflammatory cytokine produced by macrophages and is the most studied cytokine in  apoptosis and the pathophysiology of various diseases, including neurodegenerative disorders (Jackson et al., 1999). Mechanistically, the binding of TNF� to its receptor activates the NF-�B and JNK signaling pathways believed to be mediated by ROS (Okouchi et al., 2007).  A role for ROS has also been implicated in death receptor-mediated apoptosis induced by apoptosis signal-regulating kinase 1 (ASK1), an ubquitiously expressed MAP kinase kinase kinase (MAPKKK), that activates JNK and p38 MAP kinase pathways (Okouchi et al., 2007). </div> </div>

<div> <div> Free radical scavenger or antioxidant N-acetyl-L-cysteine, a thiol-containing compound, has been shown to directly reduce the levels of ROS (Aruoma et al., 1989; Kim and Sharma 2004; Poliandri et al., 2003). To confirm that Cd-induced neuronal apoptosis is indeed due to its induction of ROS generation, PC12 and SH-SY5Y cells were pretreated with NAC (5mM) for 1h, and then exposed to Cd (10 and 20μM) for 24h (Long et al., 2008). Chen et al. (2008) found that NAC dramatically blocked Cd-induced ROS generation in PC12 cells and SH-SY5Y cells.  In addition, to further quantify the protective effect of NAC on Cd-induced apoptosis via blockage of ROS in a larger cell population, they performed annexin-V-FITC and propidium iodide staining followed by flow cytometry. They found NAC alone did not affect cell viability. However, it significantly blocked Cd-induced apoptosis. Asit Rai et al. 2010 found that a metal mixture of arsenic, cadmium, and lead triggered ROS generation, reaching its peak after 1 hour of treatment.  They next investigated whether ERK1/2, JNK1/2, [Ca2+]i and ROS signaling resulted in apoptosis by reating the MM-treated astrocytes with α-tocopherol (200 μg/ml), PD98059 (10μM), BAPTA-AM (5μM), or SP600125 (10μM).  They all suppressed apoptosis suggesting that activation of ERK1/2 and JNK1/2, followed by increased [Ca2+]i and ROS generation, resulted in apoptosis in the MM-treated astrocytes. When astrocytes were exposed to H2O2 for 30 min and then incubated without H2O2 for 1–5 days, cell toxicity including apoptosis was observed (Kazuhiro et al., 2004). Furthermore, the reperfusion injury induced by Ca2+ depletion or H2O2 exposure was exacerbated by the catalase inhibitor, 3-amino-1,2,4-triazole, and the GSH synthesis inhibitors, l-buthionine-S,R-sulfoximine and xanthine, while the injury was blocked by GSH, catalase and the iron chelators, 1,10-phenanthroline and deferoxamine (Takuma et al., 1999). These findings indicate that Ca2+ reperfusion-induced apoptosis is mediated by ROS production, especially by hydroxyl radical formation (Kazuhiro et al., 2004). Exposure of cells to 5 �M iAs significantly triggered the expression of ER stress-related molecules, including: the proteins and mRNAs expression of GRP 78, CHOP, XBP-1 in a time-dependent manner (for 6–24 h) as well as the degradation of full-length (55 kDa) caspase-12 (downstream ER stress molecule). However, GRP 94 was not affected by iAs treatment. These effects of iAs-induced ER stress protein responses could be reversed by pre-treatment with NAC. Furthermore,  transfection of Neuro-2a cells with GRP 78- and CHOP-specific si-RNA, respectively, markedly reduced the protein expression levels of GRP 78 and CHOP in the cells treated with iAs and significantly attenuate the iAs-induced caspase-3, -7, and -12 activations. These results indicate that oxidative stress-mediated ER stress activation pathway is also involved in iAs-induced neuronal cell apoptosis (Tien-Hui, et al. 2014). Recent studies have shown that ROS generation induced by toxic metals (including arsenic) causes neuronal apoptosis, which is closely associated with the progression of neurodegenerative diseases (Bharathi and Jagannathan 2006; Flora et al., 2009; Gharibzadeh 2008). Okouchi et. al. (2007) found that peroxide-induced apoptosis in undifferentiated PC12 cells was mediated by an early loss of the cellular glutathione–glutathione disulfide (GSH/GSSG) redox balance that preceded an increase in Bax expression, mitochondrial-to-cytosol cytochrome c translocation, and activation of caspase 3 (Pias and Aw 2002; Pias and Aw 2002; Pias et al., 2003). Apoptosis was  ameliorated by the overexpression of mitochondrial superoxide dismutase, MnSOD (SOD2), and by pretreatment of cells with the antioxidant, N-acetyl cysteine (NAC) (23-25). As first demonstrated in mouse fibrosarcoma cells, TNF� treatment disrupts mitochondrial electron transport and  enhances ROS production (Schulze–Osthoff et al., 1992). Recent studies by Han et al. (2006) showed that modulation of the hepatocyte redox environment by ROS interfered with NF-�B signaling in TNF-induced apoptosis. Notably, cell apoptosis occurred within a certain redox window in which mild redox imbalance inhibited NF-�B activation, but not caspase activity (Okouchi et al., 2007). </div> </div>

<div> <div> ROS and/or oxidative damage can activate gene transcription and transcribed genes may be implicated in either cell survival or cell death (Klein and Ackerman 2003). The increase in reactive oxygen species at As(III) concentrations of 0.5 mg/l or more may play an apoptogenic role and/or be a consequence of events occurring during apoptosis (Rocha et al. 2011). It is generally reported that ROS cause an increase in [Ca2+]i of various cell types, which might be one of the causes for the C17.2 cells to enter apoptosis (Rocha et al. 2011). According to Hool and Corry (2007), the redox control of Ca2+ transport is due to the fact that ROS can react with the thiol groups of protein that form part of the Ca2+ transporters or channels. Alternatively, mitochondrial matrix Ca2+ overload can lead to enhanced generation of reactive oxygen species, triggering the permeability transition pore, dissipation of transmembrane mithocondrial potential, and cytochrome c release (Brookes et al., 2004). In any case, the fact that treatment with various antioxidants (vitamin E, tocopherol, and quercetin) did not rescue the cells from death by apoptosis indicates that oxidative stress was not the main cause of the observed cell death (Rocha et al. 2011). Superoxides and lipid peroxidation are increased during apoptosis induced by myriad stimuli (Bredesen 1995). However, generation of ROS may be a relatively late event, occurring after cells have embarked on a process of caspase activation (Green and Reed 1998). In this regard, attempts to study apoptosis under conditions of anoxia have demonstrated that at least some proapoptotic stimuli function in the absence or near absence of oxygen, which implies that ROSs are not the sine qua non of apoptosis (Jacobson and Raff 1995). However, ROSs can be generated under conditions of virtual anaerobiosis (Degli Esposti and McLennan 1998), and thus their role in apoptosis cannot be excluded solely on this basis (Green and Reed 1998). Okouchi et. al. (2007) found that PC12 apoptosis can be initiated by GSH/GSSG redox imbalance alone independently of ROS generation (Pias et al., 2003), suggesting that a loss of cellular  redox homeostasis is downstream of ROS signaling in neuronal cell apoptosis. </div> </div>

Moderate Unspecific Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eae17f00> AOPWiki 2023-07-18T14:52:35

2023-07-25T17:06:55

<upstream-id>ed20656b-94b8-472c-894c-cd876800a9b1</upstream-id> <downstream-id>770a76cc-1eb4-4b61-ab84-34d601c77a2e</downstream-id> In the central nervous system (CNS), neuronal apoptosis is a physiological process that is an integral part of neurogenesis, and aberrant apoptosis has been implicated in the  pathogenesis of neurodegeneration (Okouchi et al., 2007).

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

During the development of the nervous system, an excessive number of neurons is produced. This massive overproduction of neurons is followed by a programmed demise of  roughly one half of the originally produced cells (Okouchi et al., 2007). The precisely controlled process is referred to as naturally occurring neuronal death which is a highly conserved cellular  mechanism in diverse organisms, ranging from invertebrate species such as the nematode (Okouchi et al., 2007), Caenorhabditis elegans, and insects, to nearly all of the studied vertebrate species (Mishima et al., 1999). Natural neuronal death is be lieved to mold the nervous system’s cellular structure and function (Okouchi et al., 2007). As axons extend, they also bifurcate with each branch forming of its own growth cone, a process that is also regulated by apoptosis (Chen et al., 2020).  Under normal conditions, a low level of caspase maintains a balance between growth cone attraction and repulsion and inhibits axon extension; however, in PTSD, apoptosis is enhanced in key brain regions and caspase activation alters growth cone trajectory and dendritic pruning, leading to axon misguidance and dendrite degeneration. The combined outcome of these processes is the formation of fewer or incorrect synapses in PTSD that are defective in information transmission and cause abnormalities in memory and  behavior (Chen et al., 2020).

Rai, Nagendra Kumar, et al. (2013) concluded that the metal mixture arsenic, lead, and cadmium (a) induced dose-dependent modulation in the expression levels of myelin and axon proteins leading to hypo-myelination in cortex; (b) reduced axon area and myelin density in O.N.; and (c) attenuated RGC-differentiation in retina.  Apoptosis in the oligodendrocytes, axonal neurons and RGCs promoted the MM-mediated white matter damage.  Increased apoptosis in MBP and NF damage the white matter of CNS (Petzold et al., 2011; Pun et al., 2011). In consistence, Rai, Nagendra Kumar, et al. (2013) found that the impairment in postnatal oligodendrocytes and axons further increased cellular apoptosis in the brain and O.N. The neuroaxonal degeneration in the retina also involved a rise in apoptosis in Brn3b and NF. During development, Brn3b is crucial for RGC survival, and its apoptosis may affect the expression of several genes linked with axonal integrity and function (Pan, et al., 2005). Therefore, the increased MM-related apoptosis to axonal neurons in the retina could be the fallout of RGC damage (Rai et al., 2013). Altogether, the MM, in all probability, elevates the apoptosis-mediated pruning of the myelinating cells during CNS development (Rai et al., 2013). In the context of an Alzheimer's disease brain; compelling evidence of apoptotic involvement comes from studies of Rohn et al., (2002) who demonstrated the activation of mitochondrial and receptor-mediated  apoptotic pathways in AD hippocampal brain sections wherein active caspase 9 was co-localized with active caspase 8 (Okouchi et al., 2007). Moreover, the distribution of caspase-cleaved fragments of  tau suggests that the activation of caspases preceded the formation of neurofibrillary tangles in brains of AD patients (Chiueh et al., 2000). In addition, the intracellular amyloid �beta peptide 1-42 (A beta (1-42))  has been shown to induce human neuronal cell apoptosis through Bax activation that resulted in cytochrome c release and activation of caspase 6 (Zhang et al., 2002). The participation of apoptosis in disease pathogenesis in humans is supported by the demonstration of caspases 1, 3, 8, and 9, and cytochrome c activation in the brains of Huntington Disease patients (Kiechle et al., 2022; Teng et al., 2006; Sanchez et al., 1999). The involvement of hippocampal neuronal apoptosis in diabetic encephalopathy has been demonstrated in diabetic animal models (Li et al., 2005), and evidence of  classical apoptosis was associated with decreased neuronal densities, and learning and cognitive deficits (Sima and Li 2005). Cognitive impairment in BB/Wor rats is associated with evidence of classical apoptosis in the hippocampus, including DNA fragmentation, positive TUNEL staining, elevated  Bax/Bcl-x ratio, increased caspase 3 activities and decreased neuronal densities (Li et al., 2002), common features in diabetic encephalopathy. Notable among endogenous antioxidants, is estradiol, with proven effectiveness against �beta-amyloid-induced neuronal apoptosis in in vitro models of AD and PD (Gandy 2003; Yao et al., 2007).  Accelerated beta�-amyloid plaque formation in animal models of AD is associated with brain estradiol deficiency (Gandy 2003). Estradiol mediates its effect by binding to the estrogen  receptor, and targets a plethora of prosurvival cellular processes (Okouchi et al., 2007). These include neuronal expression of Bcl-2 members, upregulation of antioxidant proteins such as TRX, MnSOD, and nNOS, Akt signaling, and inhibition of transcriptional and apoptotic activity of the APPct complex (Yao et al., 2007; Bao et al., 2007; Chiueh et al., 2003; Koh et al., 2006). Melatonin is another naturally occurring neuroprotectant  that decreases amyloid fibril formation (Pappolla et al., 1998) and attenuates neuronal apoptosis in in vitro and animal models of AD and PD (Chiueh et al., 2000; Deigner et al., 2000; Matsubara et al., 2003). Its neuroprotective effects appear to be  the result of antioxidant and anti-amyloidogenic properties (Pappolla et al., 2002) and are independent of binding to membrane receptors (Okouchi et al., 2007).

While the molecular mechanisms underlying neuronal apoptosis and diabetic encephalopathy remain unresolved, it appears that diabetes-associated perturbations in the  insulin/IGF system and hyperglycemia may play prominent roles (Li and Sima 2004).

Moderate Unspecific

Moderate

All life stages

High High Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eaf56128> AOPWiki 2023-07-18T14:53:01

2023-07-26T12:35:57

<upstream-id>770a76cc-1eb4-4b61-ab84-34d601c77a2e</upstream-id> <downstream-id>eb8f7591-779c-4bf4-ba5b-b1eaac049ef8</downstream-id> Animal models of neurodegenerative diseases, in particular Alzheimer's disease, contributed to the elucidation of the link between amyloid protein and tau hyperphosphorylation and cognitive deficits. Bilateral injections of amyloid-b peptide in the frontal cortex of rats leads to progressive decline in memory and neurodegeneration in hippocampus (for review see Eslamizade et al., 2016). Recent findings have shown that soluble forms of Ab rather than insoluble forms (fibrils and plaques) are associated with memory impairment in early stages of Alzheimer's disease (for review see Salgado-Puga and Pena-Ortega, 2015). Several lines of evidence suggest that the small oligomeric forms of Ab and tau may act synergistically to promote synaptic dysfunction in Alzheimer's disease (for review see Guerrerro-Minoz et al., 2015). Some reports proposed the concept of imbalance between production and clearance of Ab42 and related Ab peptides, as an initiating factor inducing hyperphosphorylation of tau and leading to neuritic dystrophy and synaptic dysfunction (for review see Selkoe and Hardy, 2016). Recent trials of three different antibodies against amyloid peptides have suggested a slowing of cognitive decline in post hoc analyses of mild Alzheimer subjects (for review see Selkoe and Hardy, 2016). Therefore cognitive deficits may be related to the level and extent of classical Alzheimer pathology landmarks, but it is also influenced by neurodegeneration (for review see Braskie and Thompson, 2013). Indeed decreased hippocampal volume due to widespread neurodegeneration and visualized by neuroimaging appears to be a significant predictor of memory decline  (for review see Braskie and Thompson, 2016).

<div> This KER was developed, in part, as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June. In July 2023 updates were made to the then empty Taxonomic, Sex, and Life Stage Applicability fields and in the Empirical Evidence field with the addition of Wozniak et al., (2004), Allison et al., (2021), and Huang et al., (2012) studies. </div>

It is well accepted that impairment of cell function or cell loss in hippocampus will interfere with memory processes, since the hippocampus plays a key role in memory (Barker and Warburton, 2011). In Alzheimer's disease, hippocampus and entorhinal cortex are affected early in the disease process and cognitive deficit is correlated with brain atrophy (for review Braskie and Thompson, 2013).

Include consideration of temporal concordance here Pre-natal and post-natal Pb exposure affects the hippocampus and the frontal cortex (Schneider et al., 2012). Rats exposed to Pb exhibit microglial activation, and upregulation of the level of IL-1b, TNF-a and iNOS, and these pro-inflammatory factors may cause hippocampal neuronal injury as well as Long Term Potentiation (LTP) deficits, These results suggest a direct link between Pb-induced neuroinflammation, neurodegeneration in hippocampus, and memory deficit (Liu et al., 2012). These effects are reversed by minocycline, an antibiotic which decreases microglial activation, strengthening the link between neuroinflammation, neurodegeneration and memory impairment. In epidemiological studies of adults, cumulative lifetime exposure to Pb has been associated with accelerated declines in cognition (Bakulski et al., 2012). In a study aiming at determining whether serum trace metals are related to abnormal cognition in Alzheimer's disease, it was found that serum Pb levels were significantly negatively correlated with verbal memory scores (Park et al., 2014). Cognitive impaiment was observed in mice exposed to Pb as infants but not as adults, suggesting that a window of vulnerability to Pb neurotoxicity can influence Alzheimer pathogenesis and cognitive decline in old age (Bihaqui et al., 2014). Human Tg-SWDI APP transgenic mice, which over-express amyloid plaques at age of 2-3 months, received oral gavage of 50 mg/kg of Pb once daily for 6 weeks. They showed a significant increase of Abeta in the CSF, brain cortex and hippocampus associated to impaired spatial learning ability, suggesting that Pb facilitates Abeta fibril formation and participate in deposition of amyloid plaques (Gu et al., 2012), Wozniak et al., (2004) demonstrated that exposure of infant mice to EtOH on a single postnatal day (P7) induced extensive apoptotic neurodegeneration in the developing brain, and subsequent spatial learning and memory impairments that are very severe at P30, less severe if testing is first performed at P75, and minimal in later adulthood. In adulthood, working memory performance was also subtly compromised in EtOH-treated mice in a gender-dependent fashion, with the male EtOH mice being functionally impaired. Allison et al., (2021) demonstrated that the deleterious effects of AD-related pathophysiology (i.e., higher levels of CSF ptau181/Aβ42) on verbal learning and memory performance depend on the degree of global atrophy present. More specifically, individuals with a greater degree of global atrophy evidenced similar rates of decline regardless of the degree of AD pathophysiology present. In contrast, in individuals with larger global brain volumes, the presence of preclinical Alzheimer's disease was associated with steeper declines in verbal learning and memory. These findings suggest that the presence of AD biomarkers, global atrophy, or both global atrophy and AD biomarkers are all associated with greater verbal learning and memory decline in a sample of late middle-aged adults. Huang et al., (2012) findings indicated that exposure of P7 rats to ketamine leads to accelerated widespread neurodegeneration in the hippocampus. Suppression of p-PKCγ and p-ERK might be involved in neurologic damage, and this neurodegeneration could cause subsequent spatial learning abnormalities in adulthood.

There are some inconsistencies regarding the time of exposure. Some papers clearly show that early Pb exposure increases amyloid and tau pathology and cognitive decline in aging. But few studies have addressed this complex question by using an ad hoc experimental design. Other studies have descibed the effects of lifetime or long-term exposure on cognitive functions but without a precise desciption of exposure onset and duration.

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships? <table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="width:140.2pt"> Endpoints relevant for KEup Neurodegeneration in hippocampus and cortex </td> <td style="width:140.2pt"> Endpoints relevant for KEdown Impairment of learning and memory </td> <td style="width:140.2pt"> Model and treatments </td> <td style="width:140.25pt"> Reference </td> </tr> <tr> <td style="width:140.2pt">   </td> <td style="width:140.2pt">   </td> <td style="width:140.2pt">   </td> <td style="width:140.25pt">   </td> </tr> <tr> <td style="width:140.2pt">   0.5 -1x increase in amyloid peptides accumulation if early postnatal exposure </td> <td style="width:140.2pt">   Decrease in cognitive functions (Morris water maze, Y maze testing for spatial memory and memory, a hippocampus -dependent task)   </td> <td style="width:140.2pt">   Mice exposed to Pb 0.2% in drinking water from PND 1 to 20   or from PND 1-20 and from 7-9 months of age   </td> <td style="width:140.25pt">   Bihaqui et al., 2014     </td> </tr> <tr> <td style="width:140.2pt"> About 5x increase of neuronal death in hippocampus   Return to control levels in vivo and in vitro after minocycline treatment     </td> <td style="width:140.2pt"> Long Term Potentiation (LTP) was lost in Pb-treated rats and restores upon minocycline treatment     </td> <td style="width:140.2pt">   Rats exposed to Pb (100 ppm) from 24 to 80 days of age     </td> <td style="width:140.25pt">   Liu et al., 2012 </td> </tr> <tr> <td style="width:140.2pt">   About 2x more Abeta1-40 and of Abeta1-42 in CSF, cortex and hippocampus and 2x more amyloid plaque load than control   Pb co-localized with amyloid plaques. </td> <td style="width:140.2pt">   Impaired spatial learning ability  (Morris maze) </td> <td style="width:140.2pt">   Human Tg-SWDI APP mice  received by oral gavage 50mg/kg Pb once daily for 6 weeks.   Pb level in brain 60 microg/dL (similar level than those found in children, Gu et al., 2011)   </td> <td style="width:140.25pt">   Gu et al., 2012 </td> </tr> </tbody> </table>   </div>

Moderate Unspecific

Moderate

Old Age

Moderate Moderate Moderate

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eafe2088> AOPWiki 2016-11-29T18:41:36

2023-07-27T13:38:59

Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis

MEK-ERK1/2 activation leading to deficits in learning and cognition via ROS

Cataia Ives

Of the originating work: Katherine von Stackelberg (Harvard Center for Risk Analysis, Boston, MA, USA.) (Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.) Elizabeth Guzy (Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.) Tian Chu (Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.) Birgit Claus Henn (Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.) (Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA.) Of the content populated in the AOP-Wiki: Travis Karschnik (General Dynamics Information Technology, Duluth, MN, USA.)

2.5

Metal mixture activation of ERK1/2 and JNK1/2 in astrocytes leads to increased Ca2+ release (Asit Rai et al., 2010).  Alterations to calcium, an essential nutrient which is required in multiple cellular and physiological functions, such as cell adhesion, signal transduction, and neurotransmission can be expected to have downstream effects in those functions (Antonio et al., 2002).  While a variety of stimuli can trigger opening of the mitochondrial transition pore and cause apoptosis, a sustained intracellular increase in Ca2+ is one of the better-known triggers (Mattson 2000).  Mitochondria play a role in stress responses and can produce ROS when damaged. Mitochondria are indeed a major source of ROS (Yan et al., 2013).  Unchecked, excessive ROS can lead to the destruction of cellular components including lipids, protein, and DNA, and ultimately cell death via apoptosis or necrosis (Kannan and Jain 2000).  Aberrant apoptosis has been implicated in the  pathogenesis of neurodegeneration (Okouchi et al., 2007).  It is well accepted that impairment of cell function or cell loss (neurodegeneration) in hippocampus will interfere with memory processes, since the hippocampus plays a key role in memory (Barker and Warburton 2011). MEK-ERK1/2 is important in understanding uptake of metals into the brain and its relationship to deficits in learning and cognition from exposure to metals commonly detected at Superfund sites including lead, cadmium, manganese, and arsenic.  Current risk assessment guidance dictates a largely chemical-by-chemical evaluation of exposures and risks, which fails to adequately address potential interactions with other chemicals, nonchemical stressors, and genetic factors. Cumulative risk assessment methods and approaches are evolving to meet regulatory needs (MacDonell et al., 2013; Backhaus and Faust 2012; IPCS 2009), but significant challenges remain. As our understanding of complex exposures and interactions continues to grow, synthesis and integration across disciplines and studies focused on different aspects of the environmental fate–exposure–toxicology–health outcome continuum are required to assess the likelihood of adverse effects and to support cumulative risk assessment.  Environmental exposures are virtually always to complex mixtures (von Stackelberg et al., 2015).   An examination of neurodevelopmental disorders and subclinical effects using multi-domain global neurodevelopment assessments is warranted as they can have profound population level implications.  In the context of neurotoxicity, neurodevelopmental pathways in the developing human brain are not fully understood (Schubert et al., 2013; Bal-Price et al., 2015) although there are a number of commonly observed phenomena which may take part in those pathways e.g. changes in intracellular calcium, ROS generation, apoptosis, and neurotransmitter disruption.  This AOP highlights a specific set of response-response relationships using a subset of those commonly observed phenonema related to metals and metal mixture exposures leading to deficits in learning and cognition.

This AOP was developed as part of an Environmental Protection Agency effort to increase the impact of AOPs published in the peer-reviewed literature, but heretofore unrepresented in the AOP-Wiki, by facilitating their entry and update.  The originating work for this AOP was Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.  This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages. The focus of the originating work was to conduct a review of the literature on relationships between prenatal and early life exposure to mixtures of lead (Pb), arsenic (As), cadmium (Cd), and manganese (Mn) with neurodevelopmental outcomes and then use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD). Importantly, the review considered whether exposures to mixtures of metals was associated with neurodevelopment effects that were greater or less than effects from exposure to each individual metal.

A prime example of impairments in learning and memory as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD TG 426) as well as OECD TG 443 (OECD, 2018) both require testing of learning and memory (USEPA, 1998; OECD, 2007) advising to use the following tests passive avoidance, delayed-matching-to-position for the adult rat and for the infant rat, olfactory conditioning, Morris water maze, Biel or Cincinnati maze, radial arm maze, T-maze, and acquisition and retention of schedule-controlled behaviour.  These DNT Guidelines have been deemed valid to identify developmental neurotoxicity and adverse neurodevelopmental outcomes (Makris et al., 2009). Also, in the frame of the OECD GD 43 (2008) on reproductive toxicity, learning and memory testing may have potential to be applied in the context of developmental neurotoxicity studies. However, many of the learning and memory tasks used in guideline studies may not readily detect subtle impairments in cognitive function associated with modest degrees of developmental thyroid disruption (Gilbert et al., 2012).

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Moderate Unspecific

High

All life stages

Moderate Moderate Moderate

<table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:7px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:120px"> 1. Support for Biological Plausibility of KERs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:116px"> Defining Question </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:126px"> High (Strong) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:124px"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:116px"> Low (Weak) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:120px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:116px"> Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge? </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:126px"> Extensive understanding of the KER based on extensive previous documentation and broad acceptance. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:124px"> KER is plausible based on analogy to accepted biological relationships, but scientific understanding is incomplete </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:116px"> Empirical support for association between KEs , but the structural or  functional relationship between them is not understood. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:120px"> Relationship 2942: Activation of MEK, ERK1/2 (2146) leads to Increase, intracellular calcium (1339) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:482px"> Moderate Empirical evidence indicates a complex relationship between MEK, ERK1/2 activation and inhibition and Ca2+ response including Ca2+ feeding back into a ERK1/2 activation.  This relationship appears to vary across species and cell type. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:120px"> Relationship 2945: Increase, intracellular calcium (1339) leads to Increase, Mt Dysfunction (1968) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:482px"> Moderate There are both accepted associations between these two KEs and empirical evidence but the current state of understanding falls short of extensive. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:120px"> Relationship 2964: Increase, Mt Dysfunction (1968) leads to Increased, Reactive oxygen species (1115) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:482px"> High This relationship has been studied in humans and human-model rodents extensively related to age-related diseases. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:120px"> Relationship 2966: Increased, Reactive oxygen species (1115) leads to Apoptosis (1262) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:482px"> High This is a well-studied relationship across taxa where modulation of ROS and its effect on subsequent apoptosis has been examined. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:120px"> Relationship 2967: Apoptosis (1262) leads to N/A, Neurodegeneration (352) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:482px"> High This relationship has been studied in humans and human-model rodents extensively related to age-related diseases. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:120px"> Relationship 1069: N/A, Neurodegeneration (352) leads to Impairment, Learning and memory (341) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:113px; vertical-align:top; width:482px"> High This relationship has been studied in humans and human-model rodents extensively related to age-related diseases. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:120px"> Relationship 2968: Increase, intracellular calcium (1339) leads to Apoptosis (1262) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; vertical-align:top; width:482px">   </td> </tr> </tbody> </table> Life Stage Life stages applicable to this AOP encompass the full life cycle.  Many of the key events are measured in pregnant females with the adverse outcome (impairment, learning and memory) measured at all life stages. Taxonomic Applicability Most evidence for this AOP is derived from rodents and humans where rodents were selected with their ability to model human responses. Sex Applicability This AOP is applicable to all sexes.

<table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:7px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:12px; vertical-align:top; width:120px"> 2. Essentiality of KEs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:12px; vertical-align:top; width:121px"> Defining question </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:12px; vertical-align:top; width:120px"> High (Strong) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:12px; vertical-align:top; width:120px"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:12px; vertical-align:top; width:120px"> Low (Weak) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:92px; vertical-align:top; width:120px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:92px; vertical-align:top; width:121px"> Are downstream KEs and/or the AO prevented if an upstream KE is blocked? </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:92px; vertical-align:top; width:120px"> Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:92px; vertical-align:top; width:120px"> Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:92px; vertical-align:top; width:120px"> No or contradictory experimental evidence of the essentiality of any of the KEs. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:55px; vertical-align:top; width:120px"> KE 2146: Activation of MEK, ERK1/2 </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:55px; vertical-align:top; width:481px"> Moderate MEK, ERK1/2 activation is fundamental in delivering signals which regulate the cell cycle, proliferation, differentiation, adhesion, and more.  Disruptions in this activation have wide reaching effects however, there is evidence that downstream KEs can also activate this KE. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:42px; vertical-align:top; width:120px"> KE 1339: Increase, intracellular calcium </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:42px; vertical-align:top; width:481px"> High Calcium, as a primary intracellular messenger in neurons and regulator of cell responses to stress has been shown to play an integral role in subsequent KEs. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:120px"> KE 1968: Increase, mitochondrial dysfunction </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:481px"> High The ubiquity and role of mitochondria in cell function is such that changes in this KE necessitate changes in downstream KEs. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:120px"> KE 1115: Increased, Reactive oxygen species </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:481px"> High ROS has been shown to mediate apoptosis across taxa with changes in ROS levels affecting subsequent apoptosis. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:120px"> KE 1262: Apoptosis </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:481px"> High Unregulated apoptosis has been shown to affect neurodegeneration and eventual learning and memory tasks in human and rodent models. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:120px"> KE 352: N/A, Neurodegeneration </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:62px; vertical-align:top; width:481px"> High Neurodegeneration has been causally linked to learning and memory tasks in human and rodent models. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:37px; vertical-align:top; width:120px"> KE 341: Impairment, Learning and memory </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:37px; vertical-align:top; width:481px"> N/A </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:37px; vertical-align:top; width:120px"> AOP 500 </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:37px; vertical-align:top; width:481px"> High/Moderate There is evidence for manipulation of downstream KEs based on manipulation of upstream KEs in multiple KERs. </td> </tr> </tbody> </table>

<table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:7px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:120px"> 3. Empirical Support for KERs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:116px"> Defining Questions </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:126px"> High (Strong) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:124px"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:25px; vertical-align:top; width:116px"> Low (Weak) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:341px; vertical-align:top; width:120px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:341px; vertical-align:top; width:116px"> Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown? Does KEup occur at  lower doses and earlier time points than KE  down and is the incidence of KEup > than  that for KEdown? Inconsistencies? </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:341px; vertical-align:top; width:126px"> if there is dependent change in both events  following exposure to a wide range of specific stressors (extensive evidence for temporal, dose- response and incidence concordance) and no or  few data gaps or conflicting data </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:341px; vertical-align:top; width:124px"> if there is demonstrated dependent change in both events following exposure to a small number of specific stressors and some evidence inconsistent with the expected pattern that can  be explained by factors such as experimental design, technical considerations, differences  among laboratories, etc. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:341px; vertical-align:top; width:116px"> if there are limited or no studies reporting dependent change in both events following  exposure to a specific stressor (i.e., endpoints never measured in the same study  or not at all), and/or lacking evidence  of temporal or dose- response concordance, or identification of significant inconsistencies in empirical  support across taxa and species that don’t align with the expected pattern for the hypothesised AOP </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:78px; vertical-align:top; width:120px"> Relationship 2942: Activation of MEK, ERK1/2 (2146) leads to Increase, intracellular calcium (1339) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:78px; vertical-align:top; width:482px"> Moderate The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures, of which, there were many that showed dependent change in both these events following exposure.  Heavy metals like cadmium can complicate issues related to calcium levels since the metal itself can act in place of calcium in cell function. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:71px; vertical-align:top; width:120px"> Relationship 2945: Increase, intracellular calcium (1339) leads to Increase, Mt Dysfunction (1968) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:71px; vertical-align:top; width:482px"> Moderate The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures.  Some inconsistency was documented in the relationship between the two events regarding which preceded the other in different taxa and cell types. Heavy metals like cadmium can complicate issues related to calcium levels since the metal itself can act in place of calcium in cell function. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:120px"> Relationship 2964: Increase, Mt Dysfunction (1968) leads to Increased, Reactive oxygen species (1115) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:482px"> High The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures, of which, there were many that showed dependent change in both these events following exposure. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:120px"> Relationship 2966: Increased, Reactive oxygen species (1115) leads to Apoptosis (1262) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:482px"> High The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures, of which, there were many that showed dependent change in both these events following exposure. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:120px"> Relationship 2967: Apoptosis (1262) leads to N/A, Neurodegeneration (352) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:482px"> High The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures, of which, there were many that showed dependent change in both these events following exposure.  There are also numerous studies investigating this relationship in the context of neurodegenerative diseases. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:120px"> Relationship 1069: N/A, Neurodegeneration (352) leads to Impairment, Learning and memory (341) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:482px"> High The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures, of which, there were many that showed dependent change in both these events following exposure. There are also numerous studies investigating this relationship in the context of neurodegenerative diseases. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:120px"> Relationship 2968: Increase, intracellular calcium (1339) leads to Apoptosis (1262) </td> <td colspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:91px; vertical-align:top; width:482px"> High The evidence collection strategy for this AOP focused mainly on metal and metal mixture exposures, of which, there were many that showed dependent change in both these events following exposure. </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Not Specified

Asit Rai and others, Characterization of Developmental Neurotoxicity of As, Cd, and Pb Mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions, Toxicological Sciences, Volume 118, Issue 2, December 2010, Pages 586–601, https://doi.org/10.1093/toxsci/kfq266 Backhaus T, Faust M. Predictive environmental risk assessment of chemical mixtures: A conceptual framework. Environmental Science & Technology, 2012; 46(5):2564–2573. Bal-Price A, Crofton KM, Sachana M, Shafer TJ, Behl M, Forsby A, Hargreaves A, Landesmann B, Lein PJ, Louisse J, Monnet-Tschudi F, Paini A, Rolaki A, Schrattenholz A, Sunol C, van Thriel C, Whelan M, Fritsche E. Putative adverse outcome pathways relevant to neurotoxicity. Critical Reviews in Toxicology, 2015; 45(1):83–91. Barker GR, Warburton EC. 2011. When is the hippocampus involved in recognition memory? J Neurosci 31(29): 10721-10731. International Programme on Chemical Safety (IPCS),World Health Organization (WHO). Assessment of combined exposures to multiple chemicals. Report of a WHO/IPCS  International Workshop, 2009. Kannan, K, Jain, SK. Oxidative stress and apoptosis. Pathophysiology. 2000. 7:153-163. Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. "Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework," Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June. M.Teresa Antonio, Noelia López, M.Luisa Leret, Pb and Cd poisoning during development alters cerebellar and striatal function in rats, Toxicology, Volume 176, Issues 1–2, 2002, Pages 59-66, ISSN 0300-483X, https://doi.org/10.1016/S0300-483X(02)00137-3 MacDonell MM, Haroun LA, Teuschler LK, Rice GE, Hertzberg RC, Butler JP, Chang Y-S, Clark SL, John AP, Perry CS, Garcia SS, Jacob JH, Scofield MA. 2013. Cumulative risk assessment toolbox:Methods and approaches for the practitioner. Journal of Toxicology, 2013; Article ID 310904, doi:10.1155/2013/310904. Mattson, M. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1, 120–130 (2000). https://doi.org/10.1038/35040009 Okouchi, Masahiro, et al. "Neuronal apoptosis in neurodegeneration." Antioxidants & redox signaling 9.8 (2007): 1059-1096. Schubert D, Martens GJM, Kolk SM. Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders. Molecular Psychiatry, 2013; 2014:1–15. Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330. AOPWiki 2023-06-20T16:29:51

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