Increased, glutamate

2921-88-2

SBPBAQFWLVIOKP-UHFFFAOYSA-N

Chlorpyrifos

Dursban Phosphorothioic acid, O,O-diethylO-(3,5,6-trichloro-2-pyridinyl) ester Bonidel Chloroban Chloropyrifos Chloropyrifos-ethyl Chloropyriphos Chlorpyrifos E Chlorpyrifos-ethyl Clorpiran Clorpirifos Coroban Danusban Dhanusban Dursban 10CR Dursban Pro Dursban R Dursban TC Dursband Dursband 48 Emperor Ethyl chlorpyriphos Geodinfos Killmaster Lentrek Lock-On Lorsban Lorsban 50SL O,O-DIETHYL O-(3,5,6-TRICHLORO-2-PYRIDINYL PHOSPHOROTIOATE) O,O-Diethyl O-(3,5,6-trichloro-2-pyridinyl)phosphorothioate O,O-Diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate O,O-Diethyl O-(3,5,6-trichloro-2-pyridyl) thiophosphate O,O-Diethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate O,O-Diethyl-O-3,5,6-trichloro-2-pyridylphosphorothionate PHOSPHOROTHIOATE, O,O-DIETHYL O-(3,5,6-TRICHLORO- 2-PYRIDYL) Phosphorothioic acid, O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) ester Phosphorothioic acid, O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) ester Pyrifos Pyrinex Spannit Stipend suScon Green Tafaban Xinnongba CPF Chlorpyriphos O,O-Diethyl-o-(3,5,6-trichloro-2-pyridyl)phosphorothiolate

DTXSID4020458

5598-15-2

OTMOUPHCTWPNSL-UHFFFAOYSA-N

Chlorpyrifos oxon

DTXSID1038666

56-38-2

LCCNCVORNKJIRZ-UHFFFAOYSA-N

Parathion

Diethyl O-p-nitrophenyl phosphorothioate Phosphorothioic acid, O,O-diethylO-(4-nitrophenyl) ester Alleron American Cyanamid 3422 Aphamite Bayer E-605 Bladan F Diethyl 4-nitrophenyl phosphorothioate Diethyl parathion Diethyl p-nitrophenyl phosphorothionate Diethyl p-nitrophenyl thionophosphate Ethyl parathion Folidol Folidol E Folidol E-605 Folidol oil Fosferno Gearphos Lirothion Nitrostigmine Nourithion NSC 8933 O,O-Diethyl O-(4-nitrophenyl) phosphorothioate O,O-Diethyl O-(p-nitrophenyl) phosphorothioate O,O-Diethyl O-p-nitrophenyl thiophosphate O,O-Diethyl-O-(4-nitrophenyl)phosphorothioate Oleoparathene Oleoparathion Paraphos Parathene Parathion [Phosphorothioic acid, O,O-diethyl-O-(4-nitrophenyl)ester] Parathion A Parathion-ethyl paration Penncap E Phosphorothioic acid O,O-diethyl O-(4-nitrophenyl)ester Phosphorothioic acid, O,O-diethyl O-(4-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl)ester Rhodiasol Rhodiatox Selephos Super Rodiatox Thiomex Thiophos Thiophos 3422 Ethylparathion

DTXSID7021100

96-64-0

GRXKLBBBQUKJJZ-UHFFFAOYNA-N

GRXKLBBBQUKJJZ-UHFFFAOYSA-N

Soman

Soman Phosphonofluoridic acid, methyl-, 1,2,2-trimethylpropyl ester 1,2,2-Trimethylpropoxyfluorophosphine oxide 1,2,2-Trimethylpropyl methylphosphonofluoridate 3,3-Dimethyl-n-but-2-yl methylphosphonofluoridate Methyl pinacolyl phosphonofluoridate Methyl pinacolyloxy phosphorylfluoride Methylphosphonofluoridic acid 1,2,2-trimethylpropyl ester Phosphine oxide, fluoromethyl(1,2,2-trimethylpropoxy)- Phosphonofluoridic acid, P-methyl-, 1,2,2-trimethylpropyl ester Pinacoloxymethylphosphoryl fluoride Pinacolyl methylfluorophosphonate

DTXSID2031906

51-52-5

KNAHARQHSZJURB-UHFFFAOYSA-N

6-Propyl-2-thiouracil

6-Propyl-2 thiouracil (PTU) 4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo- 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone 2-Mercapto-4-hydroxy-6-n-propylpyrimidine 2-Mercapto-4-hydroxy-6-propylpyrimidine 2-Mercapto-6-propylpyrimidin-4-ol 2-Thio-4-oxo-6-propyl-1,3-pyrimidine 2-Thio-6-propyl-1,3-pyrimidin-4-one 6-n-Propyl-2-thiouracil 6-n-Propylthiouracil 6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione 6-Propylthiouracil NSC 6498 NSC 70461 Procasil Propacil propiltiouracilo Propycil Propyl-Thiorist Propylthiorit propylthiouracil Propylthiouracile Propyl-Thyracil Prothiucil Prothiurone Prothycil Prothyran Protiural Thiuragyl Thyreostat II URACIL, 4-PROPYL-2-THIO- Uracil, 6-propyl-2-thio-

DTXSID5021209

60-56-0

PMRYVIKBURPHAH-UHFFFAOYSA-N

Methimazole

2H-Imidazole-2-thione, 1,3-dihydro-1-methyl- 1,3-Dihydro-1-methyl-2H-imidazole-2-thione 1-Methyl-1,3-dihydroimidazole-2-thione 1-Methyl-1H-imidazole-2-thiol 1-Methyl-2-mercapto-1H-imidazole 1-Methyl-2-mercaptoimidazole 1-Methyl-4-imidazoline-2-thione 1-Methylimidazole-2(3H)-thione 1-Methylimidazole-2-thiol 1-Methylimidazole-2-thione 2-Mercapto-1-methyl-1H-imidazole 2-Mercapto-1-methylimidazole 2-Mercapto-N-methylimidazole 4-Imidazoline-2-thione, 1-methyl- Basolan Danantizol Favistan Frentirox Imidazole-2-thiol, 1-methyl- Mercaptazole Mercazole Mercazolyl Metazolo Methimazol Methylmercaptoimidazole Metothyrin Metothyrine Metotirin N-Methyl-2-mercaptoimidazole N-Methylimidazolethiol NSC 38608 Strumazol Tapazole Thacapzol Thiamazol thiamazole Thycapzol Thymidazol Thymidazole tiamazol

DTXSID4020820

CHEBI:29985

CHEBI L-glutamate(1-)

CL:0000129

CL microglial cell

CL:0000127

CL astrocyte

GO:0045202

GO synapse

GO:0035249

GO synaptic transmission, glutamatergic

MP:0001847

MP brain inflammation

GO:0007268

GO chemical synaptic transmission

GO:0007612

GO learning

GO:0007613

GO memory

GO:0008219

GO cell death

WIKI increased

WIKI pathological

WIKI abnormal

WIKI decreased

Chlorpyrifos Chlorpyrifos is a widely used organophosphate insecticide, which has been suspected as a risk factor for infant and childhood leukaemia after the house-hold exposure of pregnant women. According to Lu et al (2015), chlorpyrifos and its metabolite chlorpyrifos oxon exhibit an inhibitory effect on in vitro TopoII activity. Chlorpyrifos causes DNA double strand breaks as measured by the neutral Comet assay and induces MLL gene rearrangements in human fetal liver-derived CD34+ hematopoietic stem cells via TopoII ’poisoning’ as detected by the Fluorescent In Situ Hybridization (FISH) assay and in vitro isolated TopoII inhibition assay, respectively (Lu et al 2015). Chlorpyrifos also stabilizes the TopoII-DNA cleavage complex. Etoposide was used a positive reference compound in these studies.. The lowest concentration of chlorpyrifos used was 1 µM and it gave a statistically significant effect in many in vitro assays. The point of departure of etoposide, which was calculated to be 0.01 to 0.1 µM (Li et al 2014), is at least 10- fold lower than that of chlorpyrifos.   <table align="center" cellspacing="0" class="OECD" style="border-collapse:collapse; border:none; width:14.0cm"> <tbody> <tr> <td colspan="3" style="border-bottom:1px solid #4e81bd; border-left:none; border-right:none; border-top:2px solid #4e81bd; vertical-align:top"> Environmental chemicals </td> </tr> <tr> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Aromatic compounds </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> benzene, PAHs </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:none; border-top:none; vertical-align:top">  Mondrola et al.2010 </td> </tr> <tr> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Nitrosamines </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Diethylnitrosamine </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:none; border-top:none; vertical-align:top"> Thys et al 2015 </td> </tr> <tr> <td style="border-bottom:2px solid #4e81bd; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Organophosphates </td> <td style="border-bottom:2px solid #4e81bd; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Chlorpyrifos </td> <td style="border-bottom:2px solid #4e81bd; border-left:none; border-right:none; border-top:none; vertical-align:top"> Lu et al 2015, Rodriguez et al.2020 </td> </tr> </tbody> </table>

2017-04-25T04:08:02

2022-07-27T04:02:33

Chlorpyrifos oxon

2023-04-03T03:45:18

Organophosphates Organophosphate

repeated exposure

2016-11-29T18:42:20

2016-11-29T21:20:01

SARS-CoV

2020-03-01T10:42:46

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

Virus

2018-05-29T07:10:01

bacteria

2021-02-23T05:15:41

Propylthiouracil

2016-11-29T18:42:22

Iodine deficiency

2017-03-26T11:37:44

Methimazole

2016-11-29T18:42:19

WCS_7955

common ecological species zebrafish

10116

NCBI rat

10090

NCBI mouse

WCS_9606

common toxicological species human

9541

NCBI Macaca fascicularis

WCS_7227

common ecological species fruit fly

WCS_160004

common ecological species gastropods

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

10116

NCBI Rattus norvegicus

Increased, glutamate

Molecular

Glutamate (Glu) release into the synaptic cleft is primarily caused by excitatory glutamatergic neurons, however there is evidence showing astrocytes releasing glutamate through a calcium-dependent process. A mechanism explaining how astrocytes release glutamate is not well defined, but it could be released through exocytosis(Nedergaard et al. 2002). Glutamate is the main excitatory transmitter in the brain and spinal cord, where it activates both ionotropic and metabotropic receptors. There are 3 main ionotropic receptor classifications, AMPA, Kainate, and NMDA receptors, which are always excitatory (Kandel et al. 2013: 213). Excessive extracellular glutamate release overactivates these signaling pathways, and propagates the excitotoxicity caused by some nerve agents (McDonough and Shih 1997).

<ul> <li>Glutamate uptake by astrocytes and synaptic cleft concentration can be measured using liquid scintillation spectrometry and radiolabeled glutamate (H3 glutamate) (Lallement et al. 1991). Liquid scintillation spectrometry counts the activity of a radioactive sample by mixing the glutamate with a liquid scintillator (a material that fluorescens) and count photon emissions.</li> <li>Another mechanism to measure the glutamate concentration in the synaptic cleft is by microdialysis sampling. This mechanism is inexpensive and easy to use. When microdialysis is paired with other analytical methods such as High-Pressure Liquid Chromatography (HPLC), there is a higher instrumental selectivity and sensitivity (Watson et al. 2006).</li> </ul>

Taxa: Zebrafish neurotransmitter systems, including glutamate, are being used more for investigating chemical toxicity (Horzmann and Freeman 2016). Some cited sources above have data from rat experiments. Life Stage: Glutamate is functional throughout all life stages. Liu et al. (1996) suggests that immature rat brains show less glutamate-induced neurotoxicity than adult brains. Sex: Glutamate and glutamate receptors have been studied in both males and females, with similar functionality (Jafarian et al. 2019).

CL:0000540

CL neuron

High Unspecific

Not Specified

All life stages

High High

Horzmann, K. A. and J. L. Freeman (2016), "Zebrafish get connected: investigating neurotransmission targets and alterations in chemical toxicity.” Toxics 4(3). Jafarian, M., S. M. Modarres Mousavi, F. Alipour, H. Aligholi, F. Noorbakhsh, M. Ghadipasha, J. Gharehdaghi, C. Kellinghaus, S. Kovac, M. Khaleghi Ghadiri, S. G. Meuth, E. J. Speckmann, W. Stummer and A. Gorji (2019), "Cell injury and receptor expression in the epileptic human amygdala.” Neurobiology of Disease 124. DOI: 10.1016/j.nbd.2018.12.017. Kandel, E., J. Schwartz, T. Jessell, S. Siegelbaum and A. J. Hudspeth (2013), Principles of Neural Science, Fifth Edition. Blacklick, United States, McGraw-Hill Publishing. Lallement, G., P. Carpentier, A. Collet, I. Pernot-Marino, D. Baubichon and G. Blanchet (1991), "Effects of soman-induced seizures on different extracellular amino acid levels and on glutamate uptake in rat hippocampus.” Brain Research 563(1-2). DOI: 10.1016/0006-8993(91)91539-D. Liu, Z., C. E. Stafstrom, M. Sarkisian, P. Tandon, Y. Yang, A. Hori and G. L. Holmes (1996), "Age-dependent effects of glutamate toxicity in the hippocampus.” Brain Res Dev Brain Res 97(2). McDonough, J. H., Jr. and T. M. Shih (1997), "Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology.” Neurosci Biobehav Rev 21(5). Nedergaard, M., T. Takano and A. J. Hansen (2002), "Beyond the role of glutamate as a neurotransmitter.” Nature Reviews Neuroscience 3(9). DOI: 10.1038/nrn916. Watson, C. J., B. J. Venton and R. T. Kennedy (2006), "In vivo measurements of neurotransmitters by microdialysis sampling.” Analytical Chemistry 78(5). AOPWiki 2017-04-14T15:03:14

2021-10-11T14:58:11

Activation, Microglia

Microglia activation

Cellular

AOPWiki 2022-04-07T09:25:42

2022-04-07T09:25:42

Neuroinflammation

Tissue

Neuroinflammation or brain inflammation differs from peripheral inflammation in that the vascular response and the role of peripheral bone marrow-derived cells are less conspicuous. The most easily detectable feature of neuroinflammation is activation of microglial cells and astrocytes. It is evidenced by changes in shape, increased expression of certain antigens, and accumulation and proliferation of the glial cells in affected regions (Aschner, 1998; Graeber & Streit, 1990; Monnet-Tschudi et al, 2007; Streit et al, 1999; Kraft and Harry, 2011; Claycomb et al., 2013). Upon stimulation by cytokines or inflammogens (e.g. from pathogens or from damaged neurons), both glial cell types activate inflammatory signalling pathways, which result in increased expression and/or release of inflammatory mediators such as cytokines, eicosanoids, and metalloproteinases (Dong & Benveniste, 2001), as well as in the production of reactive oxygen (ROS) and nitrogen species (RNS) (Brown & Bal-Price, 2003). Different types of activation states are possible for microglia and astrocytes, resulting in pro-inflammatory or anti-inflammatory signalling and other cellular functions (such as phagocytosis) (Streit et al., 1999; Nakajima and Kohsaka, 2004). Therefore, neuroinflammation can have both neuroprotective/neuroreparative and neurodegenerative consequences (Carson et al., 2006 ; Monnet-Tschudi et al, 2007; Aguzzi et al., 2013 ; Glass et al., 2010). Under normal physiological conditions, microglial cells scan the nervous system for neuronal integrity (Nimmerjahn et al, 2005) and for invading pathogens (Aloisi, 2001; Kreutzberg, 1995; Kreutzberg, 1996; Rivest, 2009). They are the first type of cell activated (first line of defence), and can subsequently induce astrocyte activation (Falsig, 2008). Two distinct states of microglial activation have been described (Gordon, 2003; Kigerl et al, 2009; Maresz et al, 2008; Mosser & Edwards, 2008; Perego et al; Ponomarev et al, 2005; Moehle and West, 2015): The M1 state is classically triggered by interferon-gamma and/or other pro-inflammatory cytokines, and this state is characterized by increased expression of integrin alpha M (Itgam) and CD86, as well as the release of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6), and it is mostly associated with neurodegeneration. The M2 state is triggered by IL-4 and IL-13 (Maresz et al, 2008; Perego et al, 2011; Ponomarev et al, 2007) and induces the expression of mannose receptor 1 (MRC1), arginase1 (Arg 1) and Ym1/2; it is involved in repair processes. The activation of astrocytes by microglia-derived cytokines or TLR agonists resembles the microglial M1 state (Falsig 2006). Although classification of the M1/M2 polarization of microglial cells may be considered as a simplification of authentic microglial reaction states (Ransohoff, 2016), a similar polarization of reactive astrocytes has been descibed recently Liddlelow et al., 2017): Interleukin-1 alpha (IL-1alpha), TNF and subcomponent q (C1q) released by activated microglial cells induce A1-reactive astrocytes, which lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis and induce the death of neurons and oligodendrocytes.   Neuroinflammation and Brain development During brain development, microglia are known to play a critical role as shapers of neural circuits, by providing trophic factors and by remodeling and pruning synapses (Rajendran and Paolicelli, 2018). In addition to playing a role in synaptic management, microglia are important for the pruning of dying neurons and in the clearance of debris (<a href="#_ENREF_43" title="Harry, 2013 #5042">Harry, 2013</a>). Microglia seem to affect also processes associated with neuronal proliferation and differentiation (Harry and Kraft, 2012). Similarly to microglia, astrocytes have instructive roles in neurogenesis, gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, and synaptic pruning (Reemst et al., 2016). The development-dependent reactivity of microglial cells and astrocytes is not well known. Ischemic insult appears to elicit similar microglial reactivity both during brain development and in adulthood (<a href="#_ENREF_3" title="Baburamani, 2014 #6737">Baburamani et al, 2014</a>; <a href="#_ENREF_54" title="Leonardo, 2009 #6879">Leonardo & Pennypacker, 2009</a>). In contrast, treatment with lead acetate was previously shown to result in a more pronounced microglial and astrocyte reactivity in immature 3D rat brain cell cultures as compared to mature ones (<a href="#_ENREF_101" title="Zurich, 2002 #3368">Zurich et al, 2002</a>). Astrocyte reactivity was also more pronounced in immature 3D rat brain cell cultures following paraquat exposure, whereas development-dependent differences in the phenotype of reactive microglia were observed (Sandström et al., 2017). This suggests that neuroinflammation is occurring during brain development and may express a different phenotype than in adulthood, and that dysfunction of microglia and astrocyte during brain development could contribute to neurodevelopmental disorders and potentially to late-onset neuropathology (Reemst et al., 2016).   Neuroinflammation in relation to COVID19 SARS-CoV-2 patients with moderate and severe COVID-19 presented an elevated plasma levels of glial fibrillary acidic protein (GFAP), which is known as biochemical indicator of glial activation (Kanberg et al., 2020).

Neuroinflammation, i.e. the activation of glial cells can be measured by quantification of cellular markers (most commonly), or of released mediators (less common). As multiple activation states exist for the two main cell types involved, it is necessary to measure several markers of neuroinflammation: <ul> <li>Microglial activation can be detected based on the increased numbers of labeled microglia per volume element of brain tissue (due to increase of binding sites, proliferation, and immigration of cells) or on morphological changes. A specific microglial marker, used across different species, is CD11b. Alternatively various specific carbohydrate structures can be stained by lectins (e.g. IB4). Beyond that, various well-established antibodies are available to detect microglia in mouse tissue (F4/80), phagocytic microglia in rat tissue (ED1) or more generally microglia across species (Iba1). Transgenic mice are available with fluorescent proteins under the control of the CD11b promoter to easily quantify microglia without the need for specific stains.</li> <li>The most frequently used astrocyte marker is GFAP (99% of all studies) (Eng et al., 2000). This protein is highly specific for astrocytes in the brain, and antibodies are available for immunocytochemical detection. In neuroinflammatory brain regions, the stain becomes more prominent, due to an upregulation of the protein, a shape change/proliferation of the cells, and/or better accessibility of the antibody. Various histological quantification approaches can be used. Occasionally, alternative astrocytic markers, such as vimentin of the S100beta protein, have been used for staining of astrocytes (Struzynska et al., 2007). Antibodies for complement component 3 (C3), the most characteristic and highly upregulated marker of A1 neurotoxic reactive astrocytes are commercially available.</li> <li>All immunocytochemical methods can also be applied to cell culture models.</li> <li>In patients, microglial accumulation can be monitored by PET imaging, using [11C]-PK 11195 as a microglial marker (Banati et al., 2002).</li> <li>Activation of glial cells can be assessed in tissue or cell culture models also by quantification of sets of activation markers. This can for instance be done by PCR quantification of inflammatory factors, by measurement of the respective mediators, e.g. by ELISA-related immuno-quantification. Such markers include:</li> <li>Pro- and anti-inflammatory cytokine expression (IL-1β; TNF-α, Il-6, IL-4); or expression of immunostimmulatory proteins (e.g. MHC-II)</li> <li>Itgam, CD86 expression as markers of M1 microglial phenotype</li> <li>Arg1, MRC1, as markers of M2 microglial phenotype</li> </ul> For descriptions of techniques, see Falsig 2004; Lund 2006 ; Kuegler 2010; Monnet-Tschudi et al., 2011; Sandström et al., 2014; von Tobel et al.,  2014   Regulatory example using the KE Measurement of glial fibrillary acidic protein (GFAP) in brain tissue, whose increase is a marker of astrocyte reactivity, is required by the US EPA in rodent toxicity studies for fuel additives (40 CFR 79.67). It has been used on rare occasions for other toxicant evaluations.

Neuroinflammation is observed in human, monkey, rat, mouse, and zebrafish, in association with neurodegeneration or following toxicant exposure, or SARS-CoV-2 and other coronavirus infection. Some references (non-exhaustive list) are given below for illustration: Human: Vennetti et al., 2006 Monkey (Macaca fascicularis): Charleston et al., 1994, 1996 Rat: Little et al., 2012; Zurich et al., 2002; Eskes et al., 2002 Mouse: Liu et al., 2012 Zebrafish: Xu et al., 2014.

UBERON:0000955

UBERON brain

High Mixed

High

During brain development, adulthood and aging

High High Moderate Low Moderate

Aguzzi, A., Barres, B.A., Bennett, M.L., 2013. Microglia: scapegoat, saboteur, or something else? Science 339(6116), 156-161. Aloisi, F., 2001. Immune function of microglia. Glia 36, 165-179. Aschner M (1998) Immune and inflammatory responses in the CNS: modulation by astrocytes. ToxicolLett 103: 283-287 Banati, R. B. (2002). "Visualising microglial activation in vivo." Glia 40: 206-217.    Baburamani AA, Supramaniam VG, Hagberg H, Mallard C (2014) Microglia toxicity in preterm brain injury. Reprod Toxicol 48: 106-112 Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27: 325-355 Carson, M.J., Thrash, J.C., Walter, B., 2006. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 6(5), 237-245. Charleston JS, Body RL, Bolender RP, Mottet NK, Vahter ME, Burbacher TM. 1996. Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure. NeuroToxicology 17: 127-138. Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM. 1994. Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure. ToxicolApplPharmacol 129: 196-206. Claycomb, K.I., Johnson, K.M., Winokur, P.N., Sacino, A.V., Crocker, S.J., 2013. Astrocyte regulation of CNS inflammation and remyelination. Brain Sci 3(3), 1109-1127. Dong Y, Benveniste EN (2001) Immune Function of Astrocytes. Glia 36: 180-190 Eng LF, Ghirnikar RS, Lee YL (2000) Glial Fibrillary Acidic Protein: GFAP-Thirty-One Years (1969-2000). NeurochemRes 25: 1439-1451 Eskes C, Honegger P, Juillerat-Jeanneret L, Monnet-Tschudi F. 2002. Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotection via interactions with astrocytes and IL-6 release. Glia 37(1): 43-52. Falsig J, Latta M, Leist M. Defined inflammatory states in astrocyte cultures correlation with susceptibility towards CD95-driven apoptosis. J Neurochem. 2004  Jan;88(1):181-93. Falsig J, Pörzgen P, Lund S, Schrattenholz A, Leist M. The inflammatory transcriptome of reactive murine astrocytes and implications for their innate immune function. J Neurochem. 2006 Feb;96(3):893-907. Falsig J, van Beek J, Hermann C, Leist M. Molecular basis for detection of invading pathogens in the brain. J Neurosci Res. 2008 May 15;86(7):1434-47. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010). Mechanisms underlying inflammation in neurodegeneration. Cell. 2010 Mar 19;140(6):918-34. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3: 23-35 Graeber MB, Streit WJ (1990) Microglia: immune network in the CNS. Brain Pathol 1: 2-5 Harry GJ and Kraft AD (2012) Microglia in the developing brain: apotential target with lifetime effects. <a href="https://www.ncbi.nlm.nih.gov/pubmed/22322212" title="Neurotoxicology.">Neurotoxicology.</a> 33(2):191-206. Harry GJ (2013) Microglia during development and aging. Pharmacology & therapeutics 139: 313-326 Kanberg N, et al. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology. 2020 Sep 22;95(12):e1754-e1759 Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29: 13435-13444 Kraft AD, Harry GJ., Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. International Journal of Environmental research and Public Health., 2011, 8(7): 2980-3018. Kreutzberg GW (1995) Microglia, the first line of defence in brain pathologies. Arzneimttelforsch 45: 357-360 Kreutzberg GW (1996) Microglia : a sensor for pathological events in the CNS. Trends Neurosci 19: 312-318 Kuegler PB, Zimmer B, Waldmann T, Baudis B, Ilmjärv S, Hescheler J, Gaughwin P, Brundin P, Mundy W, Bal-Price AK, Schrattenholz A, Krause KH, van Thriel C, Rao MS, Kadereit S, Leist M. Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing. ALTEX. 2010;27(1):17-42 Leonardo CC, Pennypacker KR (2009) Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation 6: 13 Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638): 481-487. Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP. 2012. Trimethyltin-induced neurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis. Neurotoxicol Teratol 34(1): 72-82. Liu Y, Hu J, Wu J, Zhu C, Hui Y, Han Y, et al. 2012. alpha7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation 9: 98. Lund S, Christensen KV, Hedtjärn M, Mortensen AL, Hagberg H, Falsig J, Hasseldam H, Schrattenholz A, Pörzgen P, Leist M. The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions. J Neuroimmunol. 2006 Nov;180(1-2):71-87. Maresz K, Ponomarev ED, Barteneva N, Tan Y, Mann MK, Dittel BN (2008) IL-13 induces the expression of the alternative activation marker Ym1 in a subset of testicular macrophages. J Reprod Immunol 78: 140-148 Moehle MS, West AB (2015) M1 and M2 immune activation in Parkinson's Disease: Foe and ally? Neuroscience 302:59-73 doi:10.1016/j.neuroscience.2014.11.018 Monnet-Tschudi F, Zurich MG, Honegger P (2007) Neurotoxicant-induced inflammatory response in three-dimensional brain cell cultures. Hum Exp Toxicol 26: 339-346 Monnet-Tschudi, F., A. Defaux, et al. (2011). "Methods to assess neuroinflammation." Curr Protoc Toxicol Chapter 12: Unit12 19.          Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958-969 Nakajima K, Kohsaka S. 2004. Microglia: Neuroprotective and neurotrophic cells in the central nervous system. Current Drug Targets-Cardiovasc & Haematol Disorders 4: 65-84. Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8: 174 Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27: 10714-10721 Ponomarev ED, Shriver LP, Maresz K, Dittel BN (2005) Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J Neurosci Res 81: 374-389 <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Rajendran%20L%5BAuthor%5D&cauthor=true&cauthor_uid=29563239">Rajendran L</a>1, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Paolicelli%20RC%5BAuthor%5D&cauthor=true&cauthor_uid=29563239">Paolicelli RC</a> (2018). Microglia-Mediated Synapse Loss in Alzheimer's Disease. <a href="https://www.ncbi.nlm.nih.gov/pubmed/29563239" title="The Journal of neuroscience : the official journal of the Society for Neuroscience.">J Neurosci.</a>  38:2911-2919. Ransohoff RM. 2016. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8): 987-991. <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Reemst%20K%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Reemst K</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Noctor%20SC%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Noctor SC</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lucassen%20PJ%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Lucassen PJ</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hol%20EM%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Hol EM</a>. (2016) The Indispensable Roles of Microglia and Astrocytes during Brain Development. <a href="https://www.ncbi.nlm.nih.gov/pubmed/27877121" title="Frontiers in human neuroscience.">Front Hum Neurosci.</a>  10:566. DOI:10.3389/fnhum.2016.00566 Rivest, S., 2009. Regulation of innate immune responses in the brain. Nat Rev Immunol 9(6), 429-439. Sandstrom von Tobel, J., D. Zoia, et al. (2014). "Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures." Toxicol Lett. DOI : 10.1016/j.toxlet.2014.02.001 Sandstrom J, Broyer A, Zoia D, et al. (2017a) Potential mechanisms of development-dependent adverse effects of the herbicide paraquat in 3D rat brain cell cultures. Neurotoxicology 60:116-124 doi:10.1016/j.neuro.2017.04.010 Sandstrom J, Eggermann E, Charvet I, et al. (2017b) Development and characterization of a human embryonic stem cell-derived 3D neural tissue model for neurotoxicity testing. Toxicol In Vitro 38:124-135 doi:10.1016/j.tiv.2016.10.001 Streit, W.J., Walter, S.A., Pennell, N.A., 1999. Reactive microgliosis. Progress in Neurobiol. 57, 563-581. Struzynska L, Dabrowska-Bouta B, Koza K, Sulkowski G (2007) Inflammation-Like Glial Response in Lead-Exposed Immature Rat Brain. Toxicol Sc 95:156-162 Venneti S, Lopresti BJ, Wiley CA. 2006. The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol 80(6): 308-322. von Tobel, J. S., P. Antinori, et al. (2014). "Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype." Neurotoxicology 44C: 61-70. Xu DP, Zhang K, Zhang ZJ, Sun YW, Guo BJ, Wang YQ, et al. 2014. A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappaB and the PKCalpha/PI3-K/Akt pathways. Neurochem Int 78: 76-85. Zurich M-G, Eskes C, Honegger P, Bérode M, Monnet-Tschudi F. 2002. Maturation-dependent neurotoxicity of lead aceate in vitro: Implication of glial reactions. J Neurosc Res 70: 108-116. AOPWiki 2016-11-29T18:41:23

2022-07-15T09:54:27

Hippocampal Physiology, Altered

Tissue

The hippocampus functions as a highly integrated and organized communication and information processing network with millions of interconnections among its constitutive neurons. Neurons in the hippocampus and throughout the brain transmit and receive information largely through chemical transmission across the synaptic cleft, the space where the specialized ending of the presynaptic axon terminus of the transmitting neuron meets the specialized postsynaptic region of the neuron that is receiving that information (Kandell et al., 2012). During development (see KE: Hippocampal anatomy, Altered), as neurons reach their final destination and extend axonal processes, early patterns of electrical synaptic activity emerge in the hippocampus. These are large fields of axonal innervation of broad synaptic target sites that are replaced by more elaborate but highly targeted and refined axonal projections brought about by activity-dependent synaptic pruning and synapse elimination.  This is a classic case of the interaction between physiological and anatomical development, where anatomy develops first, and can be ‘reshaped’ by physiological function (Kutsarova et al., 2017). In the rat, excitatory processes are fully mature in area CA1 of hippocampus within 2 weeks of birth with inhibitory processes lagging begin by several weeks (Muller et al., 1989; Michelson and Lothman, 1988; Harris and Teyler, 1984). In hippocampal slices, inhibitory function in areaCA1s is first seen on postnatal day 5 and increases in strength at postnatal day 12 through 15.  In vivo studies fail to detect inhibition until postnatal day 18 with steady increase thereafter to adult levels by postnatal day 28. Synaptic plasticity in the form of long-term potentiation (LTP) is absent in the very young animal, only emerging about postnatal day 14, appearing to require the stability of both excitatory and inhibitory function to be established (Muller et al., 1989; Bekenstein and Lothman, 1991). These features of the maturation of hippocampal physiology are paralleled in dentate gyrus, but as with anatomical indices in the rat, the development of these physiological parameters lag behind the CA1 by about 1 week.

In animals, synaptic function in the hippocampus has been examined with imaging techniques, but more routinely, electrical field potentials recorded in two subregions of the hippocampus, area CA1 and dentate gyrus, have been assessed in vivo or in vitro from slices taken from naive or exposed animals. Field potentials reflect the summed synaptic response of a population of neurons following direct stimulation of input pathways across a monosynaptic connection. Changes in response amplitude due to chemical perturbations and other stressors (e.g., iodine deficiency, thyroidectomy, gene knockouts) is evidence of altered synaptic function. This can be measured in vitro, in vivo, or in hippocampal slices taken from treated animals (Gilbert and Burdette, 1995). The most common physiological measurements used to assess function of the hippocampus are excitatory synaptic transmission, inhibitory synaptic transmission, and synaptic plasticity in the form of long-term potentiation (LTP). Excitatory Synaptic Transmission: Two measures, the excitatory postsynaptic potential (EPSP) and the population spike are derived from the compound field potential at increasing stimulus strengths. The function described by the relationship of current strength (input, I) and evoked response (output, O), the I-O curve is the measure of excitatory synaptic transmission (Gilbert and Burdette, 1995). Inhibitory Synaptic Transmission: Pairs of stimulus pulses delivered in close temporal proximity is used to probe the integrity of inhibitory synaptic transmission. The response evoked by the second pulse of the pair at brief intervals (<30 msec) arrives during the activation of feedback inhibitory loops in the hippocampus. An alteration in the degree of suppression to the 2nd pulse of the pair reflects altered inhibitory synaptic function (Gilbert and Burdette, 1995). Long Term Potentiation (LTP): LTP is widely accepted to be a major component of the cellular processes that underlie learning and memory (Malenka and Bear, 2004; Bramham and Messaoudi, 2005). LTP represents, at the synapse and molecular level, the coincident firing of large numbers of neurons that are engaged during a learning event. The persistence of LTP emulates the duration of the memory. Synaptic plasticity in the form of LTP is assessed by delivering trains of high frequency stimulation to induce a prolonged augmentation of synaptic response. Probe stimuli at midrange stimulus strengths are delivered before and after application of LTP-inducing trains. The degree of increase in EPSP and PS amplitude to the probe stimulus after train application, and the duration of the induced synaptic enhancement are metrics of LTP. Additionally, contrasting I-O functions of excitatory synaptic transmission before and after (hours to days) LTP is induced is also a common measure of LTP maintanence (Bramham and Messaoudi, 2005; Kandell et al., 2012; Malenka and Bear, 2004). Synaptic function in the human hippocampus has been assessed using electroencephalography (EEG) and functional neuroimaging techniques (Clapp et al., 2012). EEG is a measure of electrical activity over many brain regions but primarily from the cortex using small flat metal discs (electrodes) placed over the surface of the skull. It is a readily available test that provides evidence of how the brain functions over time. Functional magnetic resonance imaging or functional MRI (fMRI) uses MRI technology to measure brain activity by detecting associated changes in blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. Positron emission tomography (PET) is a functional imaging technique that detects pairs of gamma rays emitted indirectly by a radionuclide (tracer) injected into the body (Tietze, 2012; McCarthy, 1995). Like fMRI, PET scans indirectly measure blood flow to different parts of the brain – the higher the blood flow, the greater the activation (McCarthy, 1995). These techniques have been widely applied in clinical and research settings to assess learning and memory in humans and can provide information targeted to hippocampal functionality (McCarthy, 1995; Smith and Jonides, 1997; Willoughby et al., 2014; Wheeler et al., 2015; Gilbert et al., 1998). Assays of this type are fit for purpose, have been well accepted in the literature, and are reproducible across laboratories. The assay directly measures the key event of altered neurophysiological function.

The majority of evidence for this key event come from work in rodent species (i.e., rat, mouse). There is a moderate amount of evidence from other species, including humans (Clapp et al., 2012).

UBERON:0000955

UBERON brain

High Female High Male

High

During brain development

Moderate High High

Bekenstein JW, Lothman EW. An in vivo study of the ontogeny of long-term potentiation (LTP) in the CA1 region and in the dentate gyrus of the rat hippocampal formation. Brain Res Dev Brain Res. 1991 Nov 19;63(1-2):245- Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99-125. Clapp WC, Hamm JP, Kirk IJ, Teyler TJ. Translating long-term potentiation from animals to humans: a novel method for noninvasive assessment of cortical plasticity. Biol Psychiatry. 2012 Mar 15;71(6):496-502. Gilbert, M.E. and Burdette, L.J. (1995). Hippocampal Field Potentials: A Model System to Characterize Neurotoxicity. In Neurotoxicology: Approaches and Methods. L.W Chang and W. Slikker (Eds). Academic Press:New York, 183-204. Gilbert ME, Mack CM. Chronic lead exposure accelerates decay of long-term potentiation in rat dentate gyrus in vivo. Brain Res. 1998 Apr 6;789(1):139-49. Harris KM, Teyler TJ. Developmental onset of long-term potentiation in area CA1 of the rat hippocampus. J Physiol. 1984. 346:27-48. Kandell, E., Schwartz, J., Siegelbaum, A. and Hudspeth, A.J.  (2012) Principles of Neural Science, 5th Edition.  Elsevier, North Holland. Kutsarova E, Munz M, Ruthazer ES.  Rules for Shaping Neural Connections in the Developing Brain.  Front Neural Circuits. 2017 Jan 10;10:111. doi: 10.3389/fncir.2016.00111. Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5-21. McCarthy, G. (1995) Review: Functional Neuroimaging and Memory. The Neuroscientist, 1:155-163. Michelson HB, Lothman EW. An in vivo electrophysiological study of the ontogeny of excitatory and inhibitory processes in the rat hippocampus. Brain Res Dev Brain Res. 1989 May 1;47(1):113-22. Muller D, Oliver M, Lynch G. Developmental changes in synaptic properties in hippocampus of neonatal rats. Brain Res Dev Brain Res. 1989 Sep 1;49(1):105-14. Smith, E and Jonides, J. (1997). Working Memory: A View from Neuroimaging. Cognitive Psychology, 33:5-42. Tietze, KJ. (2012). Review of Laboratory and Diagnostic Tests- Positron Emission Tomography. In Clinical Sills for Pharmacists, 3rd Edition, pp 86-122.  Wheeler SM, McLelland VC, Sheard E, McAndrews MP, Rovet JF (2015) Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism. Front Endocrinol (Lausanne) 6:163. Willoughby KA, McAndrews MP, Rovet JF (2014) Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid 24:576-584. AOPWiki 2016-11-29T18:41:26

2018-08-11T09:41:37

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. The development of autobiographical memory. Annu Rev Psychol. 2011;62:559-82. Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787. Gilbert ME, Rovet J, Chen Z, Koibuchi N. (2012) Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology 33: 842-52. Gilbert ME, Sui L (2006) Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22. Guirfa, M., Sandoz, J.C., 2012. Invertebrate learning and memory: fifty years of olfactory conditioning of the proboscis extension response in honeybees. Learn. Mem. 19 (2), 54–66. Herold, C, Lässer, MM, Schmid, LA, Seidl, U, Kong, L, Fellhauer, I, Thomann,PA, Essig, M and Schröder, J. (2015). 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. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death. STOTEN. 584-585, 751-775. Lezak MD (1984) Neuropsychological assessment in behavioral toxicology--developing techniques and interpretative issues. Scand J Work Environ Health 10 Suppl 1:25-29. Lezak MD (1994) Domains of behavior from a neuropsychological perspective: the whole story. Nebr Symp Motiv 41:23-55. Makris SL, Raffaele K, Allen S, Bowers WJ, Hass U, Alleva E, Calamandrei G, Sheets L, Amcoff P, Delrue N, Crofton KM.(2009) A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect.  Jan;117(1):17-25. Menzel, R., 2012. The honeybee as a model for understanding the basis of cognition. Nat. Rev. Neurosci. 13 (11), 758–768. Mitchell AS, Dalrymple-Alford JC, Christie MA. (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. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372-376. Stanton ME, Spear LP (1990) Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol Teratol 12:261-267. Talley, JL. (1986). Memory in learning disabled children: Digit span and eh Rey Auditory verbal learning test. Archives of Clinical Neuropsychology, Elseiver. <div> <div>T.M. Wang, C.W. Su, H.F. Liao, L.Y. Lin, K.S. Chou, S.H. Lin The standardization of the comprehensive developmental inventory for infants and toddlers Psychol. Test., 45 (1998), pp. 19-46</div> <div> </div> <div>Toscano CD, Guilarte TR. (2005) Lead neurotoxicity: From exposure to molecular effects. Brain Res Rev. 49: 529-554.</div> </div> U.S.EPA. 1998. Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study. EPA Document 712-C-98-239.Office of Prevention Pesticides and Toxic Substances. Vorhees CV, Williams MT (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-332. <div> <div>Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014 Jul;9:1-11.</div> </div>   AOPWiki 2016-11-29T18:41:24

2023-06-26T12:44:45

decreased, Bcl-2 expression

Molecular

AOPWiki 2023-04-04T10:31:40

2023-04-04T10:31:40

increased, Bax expression

Molecular

AOPWiki 2023-04-04T10:32:48

2023-04-04T10:32:48

decreased, Intellectual Quotient

decreased, IQ

Population

AOPWiki 2023-04-04T10:27:38

2023-04-04T10:27:38

increased, Economic Burden

Population

AOPWiki 2023-04-04T10:29:22

2023-04-04T10:29:22

Cell injury/death

Cellular

Two types of cell death can be distinguished by morphological features, although it is likely that these are two ends of a spectrum with possible intermediate forms. Apoptosis involves shrinkage, nuclear disassembly, and fragmentation of the cell into discrete bodies with intact plasma membranes. These are rapidly phagocytosed by neighbouring cells. An important feature of apoptosis is the requirement for adenosine triphosphate (ATP) to initiate the execution phase. In contrast, necrotic cell death is characterized by cell swelling and lysis. This is usually a consequence of profound loss of mitochondrial function and resultant ATP depletion, leading to loss of ion homeostasis, including volume regulation, and increased intracellular Ca2+. The latter activates a number of nonspecific hydrolases (i.e., proteases, nucleases, and phospholipases) as well as calcium dependent kinases. Activation of calpain I, the Ca2+-dependent cysteine protease cleaves the death-promoting Bcl-2 family members Bid and Bax which translocate to mitochondrial membranes, resulting in release of truncated apoptosis-inducing factor (tAIF), cytochrome c and endonuclease in the case of Bid and cytocrome c in the case of Bax. tAIF translocates to cell nuclei, and together with cyclophilin A and phosphorylated histone H2AX (γH2AX) is responsible for DNA cleavage, a feature of programmed necrosis. Activated calpain I has also been shown to cleave the plasma membrane Na+–Ca2+ exchanger, which leads to build-up of intracellular Ca2+, which is the source of additional increased intracellular Ca2+. Cytochrome c in cellular apoptosis is a component of the apoptosome. DNA damage activates nuclear poly(ADP-ribose) polymerase-1(PARP-1), a DNA repair enzyme. PARP-1 forms poly(ADP-ribose) polymers, to repair DNA, but when DNA damage is extensive, PAR accumulates, exits cell nuclei and travels to mitochondrial membranes, where it, like calpain I, is involved in AIF release from mitochondria. A fundamental distinction between necrosis and apoptosis is the loss of plasma membrane integrity; this is integral to the former but not the latter. As a consequence, lytic release of cellular constituents promotes a local inflammatory reaction, whereas the rapid removal of apoptotic bodies minimizes such a reaction. The distinction between the two modes of death is easily accomplished in vitro but not in vivo. Thus, although claims that certain drugs induce apoptosis have been made, these are relatively unconvincing. DNA fragmentation can occur in necrosis, leading to positive TUNEL staining (see explanation below). Conversely, when apoptosis is massive, it can exceed the capacity for rapid phagocytosis, resulting in the eventual appearance of secondary necrosis. Two alternative pathways - either extrinsic (receptor-mediated) or intrinsic (mitochondria-mediated) - lead to apoptotic cell death. The initiation of cell death begins either at the plasma membrane with the binding of TNF or FasL to their cognate receptors or within the cell. The latter is due to the occurrence of intracellular stress in the form of biochemical events such as oxidative stress, redox changes, covalent binding, lipid peroxidation, and consequent functional effects on mitochondria, endoplasmic reticulum, microtubules, cytoskeleton, or DNA. The intrinsic mitochondrial pathway involves the initiator, caspase-9, which, when activated, forms an “apoptosome” in the cytosol, together with cytochrome c, which translocates from mitochondria, Apaf-1 and dATP. The apoptosome activates caspase-3, the central effector caspase, which in turn activates downstream factors that are responsible for the apoptotic death of a cell (Fujikawa, 2015). Intracellular stress either directly affects mitochondria or can lead to effects on other organelles, which then send signals to the mitochondria to recruit participation in the death process (Fujikawa, 2015; Malhi et al., 2010). Constitutively expressed nitric oxide synthase (nNOS) is a Ca2+-dependent cytosolic enzyme that forms nitric oxide (NO) from L-arginine, and NO reacts with the free radical such as superoxide (O2−) to form the very toxic free radical peroxynitrite (ONOO−). Free radicals such as ONOO−, O2 − and hydroxyl radical (OH−) damage cellular membranes and intracellular proteins, enzymes and DNA (Fujikawa, 2015; Malhi et al., 2010; Kaplowitz, 2002; Kroemer et al., 2009).

Necrosis: Lactate dehydrogenase (LDH) is a soluble cytoplasmic enzyme that is present in almost all cells and is released into extracellular space when the plasma membrane is damaged. To detect the leakage of LDH into cell culture medium, a tetrazolium salt is used in this assay. In the first step, LDH produces reduced nicotinamide adenine dinucleotide (NADH) when it catalyzes the oxidation of lactate to pyruvate. In the second step, a tetrazolium salt is converted to a colored formazan product using newly synthesized NADH in the presence of an electron acceptor. The amount of formazan product can be colorimetrically quantified by standard spectroscopy. Because of the linearity of the assay, it can be used to enumerate the percentage of necrotic cells in a sample (Chan et al., 2013).  The MTT assay is a colorimetric assay for assessing cell viability. NAD(P)H-dependent cellular oxidoreductase enzymes may reflect the number of viable cells present. These enzymes are capable of reducing the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to its insoluble formazan, which has a purple color. Other closely related tetrazolium dyes include XTT, MTS and the WSTs. Tetrazolium dye assays can also be used to measure cytotoxicity (loss of viable cells) or cytostatic activity (shift from proliferation to quiescence) of potential medicinal agents and toxic materials. MTT assays are usually done in the dark since the MTT reagent is sensitive to light (Berridgeet al.,2005). Propidium iodide (PI) is an intercalating agent and a fluorescent molecule used to stain necrotic cells. It is cell membrane impermeant so it stains only those cells where the cell membrane is destroyed. When PI is bound to nucleic acids, the fluorescence excitation maximum is 535 nm and the emission maximum is 617 nm (Moore et al.,1998) Alamar Blue (resazurin) is a fluorescent dye. The oxidized blue non fluorescent Alamar blue is reduced to a pink fluorescent dye in the medium by cell activity (O'Brien et al., 2000) (12). Neutral red uptake, which is based on the ability of viable cells to incorporate and bind the supravital dye neutral red in lysosomes (Repetto et al., 2008)(13). Moreover, quantification of ATP, signaling the presence of metabolically active cells, can be performed (CellTiter-Glo; Promega). ATP assay: Quantification of ATP, signaling the presence of metabolically active cells (CellTiter-Glo; Promega). Apoptosis: TUNEL is a common method for detecting DNA fragmentation that results from apoptotic signalling cascades. The assay relies on the presence of nicks in the DNA which can be identified by terminal deoxynucleotidyl transferase or TdT, an enzyme that will catalyze the addition of dUTPs that are secondarily labeled with a marker. It may also label cells that have suffered severe DNA damage. Caspase activity assays measured by fluorescence. During apoptosis, mainly caspase-3 and -7 cleave PARP to yield an 85 kDa and a 25 kDa fragment. PARP cleavage is considered to be one of the classical characteristics of apoptosis. Antibodies to the 85 kDa fragment of cleaved PARP or to caspase-3 both serve as markers for apoptotic cells that can be monitored using immunofluorescence (Li, Peng et al., 2004). Hoechst 33342 staining: Hoechst dyes are cell-permeable and bind to DNA in live or fixed cells. Therefore, these stains are often called supravital, which means that cells survive a treatment with these compounds. The stained, condensed or fragmented DNA is a marker of apoptosis (Loo, 2002; Kubbies and Rabinovitch, 1983).  Acridine Orange/Ethidium Bromide staining is used to visualize nuclear changes and apoptotic body formation that are characteristic of apoptosis. Cells are viewed under a fluorescence microscope and counted to quantify apoptosis.

Cell death is an universal event occurring in cells of any species (Fink and Cookson,2005).

CL:0000255

CL eukaryotic cell

Not Specified Unspecific

Not Specified

All life stages

High High High High

<ul> <li>Fujikawa, D.G. (2015), The role of excitotoxic programmed necrosis in acute brain injury, Comput Struct Biotechnol J, vol. 13, pp. 212-221.</li> <li>Malhi, H. et al. (2010), Hepatocyte death: a clear and present danger, Physiol Rev, vol. 90, no. 3, pp. 1165-1194.</li> <li>Kaplowitz, N. (2002), Biochemical and Cellular Mechanisms of Toxic Liver Injury, Semin Liver Dis, vol. 22, no. 2, <a class="external free" href="http://www.medscape.com/viewarticle/433631" rel="nofollow" target="_blank">http://www.medscape.com/viewarticle/433631</a> (accessed on 20 January 2016).</li> <li>Kroemer, G. et al., (2009), Classification of cell death: recommendations of the Nomenclature Committee on Cell Death, Cell Death Differ, vol. 16, no. 1, pp. 3-11.</li> <li>Chan, F.K., K. Moriwaki and M.J. De Rosa (2013), Detection of necrosis by release of lactate dehydrogenase (LDH) activity, Methods Mol Biol, vol. 979, pp. 65–70.</li> <li>Berridge, M.V., P.M. Herst and A.S. Tan (2005), Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnology Annual Review, vol. 11, pp 127-152.</li> <li>Moore, A, et al.(1998), Simultaneous measurement of cell cycle and apoptotic cell death,Methods Cell Biol, vol. 57, pp. 265–278.</li> <li>Li, Peng et al. (2004), Mitochondrial activation of apoptosis, Cell, vol. 116, no. 2 Suppl,pp. S57-59, 2 p following S59.</li> <li>Loo, D.T. (2002), TUNEL Assay an overview of techniques, Methods in Molecular Biology, vol. 203: In Situ Detection of DNA Damage, chapter 2, Didenko VV (ed.), Humana Press Inc.</li> <li>Kubbies, M. and P.S. Rabinovitch (1983), Flow cytometric analysis of factors which influence the BrdUrd-Hoechst quenching effect in cultivated human fibroblasts and lymphocytes, Cytometry, vol. 3, no. 4, pp. 276–281.</li> <li>Fink, S.L. and B.T. Cookson (2005), Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells, Infect Immun, vol. 73, no. 4, pp.1907-1916.</li> <li>O'Brien J, Wilson I, Orton T, Pognan F. 2000. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. European journal of biochemistry / FEBS 267(17): 5421-5426.</li> <li>Repetto G, del Peso A, Zurita JL. 2008. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nature protocols 3(7): 1125-1131.</li> </ul> AOPWiki 2016-11-29T18:41:22

2022-07-15T09:46:25

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4300048530> AOPWiki 2023-04-04T10:36:14

2023-04-04T10:36:14

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4300241530> AOPWiki 2023-04-04T10:36:48

2023-04-04T10:36:48

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308a4bf70> AOPWiki 2023-04-03T06:05:05

2023-04-03T06:05:05

<upstream-id>6af32d2e-89f6-49aa-bab9-e82a47a07c10</upstream-id> <downstream-id>d053b7d2-6867-4dbf-825f-b5f53be7a3e1</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308a71220> AOPWiki 2023-04-04T10:37:50

2023-04-04T10:37:50

<upstream-id>2796f2bf-fcd2-4e46-bac7-4ca983d97fad</upstream-id> <downstream-id>d053b7d2-6867-4dbf-825f-b5f53be7a3e1</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc76fbf0> AOPWiki 2023-04-04T10:38:16

2023-04-04T10:38:16

<upstream-id>62d29bf9-315f-45b9-8963-4e212be7ebdf</upstream-id> <downstream-id>2a1803bc-1dec-4730-bc38-28c5ee45eb38</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc795670> AOPWiki 2023-04-03T06:06:12

2023-04-03T06:06:12

<upstream-id>2a1803bc-1dec-4730-bc38-28c5ee45eb38</upstream-id> <downstream-id>d053b7d2-6867-4dbf-825f-b5f53be7a3e1</downstream-id> Cells of the innate (microglia and astrocytes) and of the adaptive (infiltrating monocytes and lymphocytes) immune system of the brain have various ways to kill neighboring cells. This is in part due to evolutionary-conserved mechanisms evolved to kill virus-infected cells or tumor cells; in part it is a bystander phenomenon due to the release of mediators that should activate other cells and contribute to the killing of invading micro-organisms. An exaggerated or unbalanced activation of immune cells can thus lead to parenchymal (neuronal) cell death (Gehrmann et al., 1995). Mediators known to have such effects comprise components of the complement system and cytokines/death receptor ligands triggering programmed cell death (Dong and Benveniste, 2001). Various secreted proteases (e.g. matrix metalloproteases), lipid mediators (e.g. ceramide or gangliosides) or reactive oxygen species can contribute to bystander death of neurons (Chao et al., 1995; Nakajima et al., 2002; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013). The equimolar production of superoxide and NO from glial cells can lead to high steady levels of peroxynitrite, which is a very potent cytotoxicant (Yuste et al., 2015). Already stressed neurons, with an impaired anti-oxidant defence system, are more sensitive to such mediators (Xu et al., 2015). Healthy cells continuously display anti "eat-me" signals, while damaged and stressed neurons/neurites display "eat-me" signals that may be recognized by microglia as signals to start phagocytosis (Neher et al., 2012) or by astrocytes (Wakida et al., 2018; Byun and Chung, 2018; Gomez-Arboledas et al., 2018; Morizawa et al., 2017). Reactive astrocytes are also able to release neurotoxic molecules (Mena and Garcia de Ybenes, 2008; Niranjan, 2014). However, astrocytes may also be protective due to their capacity to quench free radicals and secrete neurotrophic factors. The activation of astrocytes may reduce neurotrophic support to neurons (for review, Mena and Garcia de Ybenes, 2008).

In vitro co-culture experiments have demonstrated that reactive glial cells (microglia and astrocytes) can kill neurons (Chao et al., 1995; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013) and that interventions with e.g. i-NOS inhibition can rescue the neurons (Yadav et al., 2012; Brzozowski et al., 2015). Drugs that block Toll like receptor pathways, which are expressed by glial cells have been proven to be protective by decreasing ROS and RNS production (Lucas et al., 2013). Reactive microglia can remove synapses, a process known as synapse stripping (Banati et al., 1993; Kettenmann et al., 2013). Reactive astrocytes were also associated with neurite and synapse reduction (Calvo-Ochoa et al., 2014). Microglia can modulate synapse plasticity, an effect mediated by cytokines. During development, microglia can promote synaptogenesis or engulf synapses, a process known as synaptic pruning (for review, Jebelli et al., 2015). It is hypothesized that alterations in microglia functioning during synapse formation and maturation of the brain can have significant long-term effects on the final established neural circuits (for review, Harry and Kraft, 2012). The fact that astrocytes can receive and respond to the synaptic information produced by neuronal activity, owing to their expression of a wide range of neurotransmitter receptors, has given rise to the concept of tripartite synapse (for review, Perez-Alvarez and Araque, 2013; Bezzi and Volterra, 2001). Pro-inflammatory cytokines, such as TNF-a, IL-1b and IL-6, which are produced by reactive astrocytes, are on one side implicated in synapse formation and scaling, long-term potentiation and neurogenesis (for review, Bilbo and Schwartz, 2009) and on the other side can kill neurons (Chao et al., 1995; Kraft and Harry, 2011). Taken together, this suggests that neuron-glia interactions are tightly regulated and that an imbalance, such as increased or long-term release of these inflammatory mediators may lead to deleterious effects on neurons.

Mercury Mercury accumulates in the brain particularly in astrocytes and induce astrocyte swelling, excitatory amino acid release and decreased anti-oxidant protections (Shanker et al., 2003; Allen et al., 2001), features that are also observed in reactive astrocytes. Due to the central role of astrocytes for neuronal function (control of water transport, production of trophic factors, of anti-oxidants, tri-partite synapse,… (Ximeres da Silva, 2016; Bezzi and Volterra, 2001; Hertz and Zielke, 2004; Sidoryk-Wegrzynowicz et al., 2011), it is thought that neuronal dysfunction may be secondary to disturbance in astrocytes (Aschner et al., 2007). Perinatal exposure (GD7-PD21) of rat to MeHgCl (0.5 mg/kg bw/day) in drinking water lead to gliosis in cerebellum of immature rats (PD21) without affecting the cholinergic system. In contrast, at PD36, astrogliosis was accompanied by an increase of muscarinic M2-immunopositive Bergman cells and a lack of M3 muscarinic receptors in the molecular layer. These results suggest that astrogliosis which is observed first at PD21 may be responsible of the delayed effects of mercury on neurons (Roda et al., 2008). Developmental exposure of mice from GD8 to PD21 to 50 mM HgCl2 in maternal drinking water: Female offsprings exhibited higher neuroinflammation which is associated with altered social behavior (Zhang et al., 2013). MG17, a novel triazole derivative, was able to reduce mercury-induced upregulation of IL-1b, IL-6 and TNF-a (measured by RT-PCR) and proved to be protective against mercury-induced neurodegeneration (Matharasala et al., 2017). Adult rats exposed to MeHg (5mg/kg bw) for 12 consecutive days exhibited piknotic nuclei in cerebellar granule cells, what was reverted by a co-administration  of CA074 an inhibitor of cathepsin released by activated microglia. These observations strongly suggest that the mercury–induced neuronal pathological changes are secondary to microglial activation (Sakamoto et al., 2008).   Acrylamide Rats exposed to acrylamide (20 mg/kg bw for 4 weeks) together with farmesol (sequiterpene) showed a downregulation of astrogliosis (i.e. decreased GFAP) and of microgliosis (i.e. decreased Iba1) and of TNF-a, Il-1b and i-NOS in cortex, hippocampus and striatum. This was associated with a marked improvement in motor coordination and a decrease in markers of oxidative stress, as compared to rats exposed to acrylamide alone (Santhanasabapathy et al., 2015).

In 3D rat brain cell-cultures, co-administration of the pro-inflammatory cytokine IL-6 (10 ng/ml) together with non-cytotoxic concentrations of MeHgCl (3 x 10-7 M) for 10 days protected from the mercury-induced decreased in MAP2 immunostaining, suggesting a positive effect of IL-6, in accord with its descibed trophic activity (Eskes et al., 2002).

The consequences of neuroinflammation depends rather on the balance between the pro-inflammatory/neurodegenerative and anti-inflammatory/alternative/neuro-reparative side, of the duration and probably of the cellular context. There is not enough literature describing an inhibition of mercury-induced neuroinflammation and the potential protection on neurons.

Not Specified Male Not Specified Female

Not Specified

All life stages

High High

Most experimental evidences derived from mouse and rat studies.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43006fbd78> AOPWiki 2017-11-09T04:11:55

2019-11-07T10:27:59

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430074cb38> AOPWiki 2023-04-05T03:48:28

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43007fbcf0> AOPWiki 2023-04-03T06:07:00

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4310b6da18> AOPWiki 2023-04-04T10:39:52

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4310c5dc48> AOPWiki 2023-04-04T10:35:28

2023-04-04T10:35:28

Increased glutamate leads to economic burden through reduced IQ and non-cholinergic mechanisms

Increased glutamate to economic burden

Arthur Author

Thibaut Coustillet1, Xavier Coumoul1, Anne-Sophie Villégier2,3, Michèle Bisson4, Florence Zeman2,3, Karine Audouze1   1Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France. 2Unité Toxicologie Expérimentale et Modélisation, Institut National de l’Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France. 3PériTox, UMR_I 01, CURS, Université de Picardie Jules Verne, Chemin du Thil, 80025 Amiens, France. 4Unité d’Expertise en Toxicologie/Ecotoxicologie des Substances, Institut National de l’Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France.

2.5

Prenatal and neonatal periods are windows of vulnerability to environmental chemical contaminants. A growing number of epidemiological and toxicological studies suggest that exposure to pesticides during these periods may impact the health of children at birth as well as their development, with potential delayed adverse effects. An AOP initiated after exposure to organophosphate pesticides such as chlorpyrifos (CPF) leading to a decrease of Intellectual Quotient (IQ) passing through non-cholinergic mechanisms was built using expert knowledges and artificial intelligence tool (the third-party tool AOP-helpFinder). Indeed, despite the well-known mode of action of organophosphates as acetylcholinesterase (AchE) inhibitors, some studies have shown adverse effects on neurodevelopment at doses insufficient for AchE inhibition, thus suggesting the involvement of so-called non-cholinergic mechanisms. Moreover, we have introduced a new concept that allows to link the AO to a country outcome (CO) by linking the KE ‘decrease of IQ’ to the KE ‘economic burden’, as an increasing number of studies and models showed the long-term economic impacts of stress exposure. Following, the ‘population’ level of organization of the AOP (i.e. adverse effects occur on several individuals in the same community), we propose to show that this AOP can have effects at a country scale.

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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<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>

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AOPWiki 2023-03-31T10:13:27

2023-09-25T16:27:14