Binding of substrate, endocytic receptor

1403-66-3

Gentamicin

Gentacycol Gentalline gentamicina gentamicine GENTAMYCIN Gentavet Lyramycin Oksitselanim Septigen Centicin Gentamycins

DTXSID5034642

32986-56-4

NLVFBUXFDBBNBW-PBSUHMDJSA-N

Tobramycin

D-Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→4)]-2-deoxy- 3'-Deoxykanamycin B Deoxykanamycin B D-Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-O-[2,6-diamino- 2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→4)]-2-deoxy- Nebramycin 6 Nebramycin factor 6 Nebramycin VI NSC 180514 O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxystreptamine O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1→6)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→4)]-2-deoxy-D-streptamine Streptamine, O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-, D- Tobracin Tobradistin Tobralex Tobramax Tobramaxin Tobramicin tobramicina Tobramycetin tobramycine

DTXSID8023680

1404-90-6

MYPYJXKWCTUITO-KIIOPKALSA-N

Vancomycin

Diatracin Vancocin Vancocine vancomicina vancomycine

DTXSID0042664

1404-26-8

Polymyxin B

polymyxine B

DTXSID1048467

1066-17-7

LUTPDAWYUNZUTI-BQTIBMHRSA-N

Colistin

Colimycin Colisticina colistina colistine Colivet Coly-Mycin Kangdisu Polymyxin E Totazina

DTXSID1040663

308060-74-4

Albumin

DTXSID1040409

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

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

DTXSID1023940

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

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

DTXSID1042522

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag Nanopaste NPS-J 90 Ag Sphere 2 Ag-C-GS Algaedyn Arctic Silver 3 Argentum Astroflake 5 Carey Lea silver Colloidal silver Dotite XA 208 Du Pont 4943 ECM 100AF4810 Enlight 600 Enlight silver plate 600 Epinall Finesphere SVND 102 Fordel DC FP 5369-502 Jelcon SH 1 Jungindai Takasago 300 KS (metal) LCP 1-19SFS Metz 3000-1 Nanomelt AGC-A Nanomelt Ag-XA 301 Nanomelt Ag-XF 301 Nanomelt Ag-XF 301H Nanopaste NPS-J 90 Perfect Silver Puff Silver X 1200 RT 1710S-C1 SD (metal) Shell Silver Silbest E 20 Silbest F 20 Silbest J 18 Silbest TC 12 Silbest TC 20E Silbest TC 25A Silbest TCG 1 Silbest TCG 7 Silcoat AgC 103 Silcoat AgC 2011 Silcoat AgC 209 Silcoat AgC 2190 Silcoat AgC 222 Silcoat AgC 2411 Silcoat AgC 74T Silcoat AgC-A Silcoat AgC-AO Silcoat AgC-B Silcoat AgC-BO Silcoat AgC-D Silcoat AgC-G Silcoat AgC-GS Silcoat AgC-L Silcoat AgC-O Silcoat GS Silcoat RF 200 Silflake 135 Silsphere 514 Silver atom Silver element Silver Flake 1 Silver Flake 25 Silver Flake 52 Silver Flake 7A SILVER FLAKES Silver metal Silvest TCG 11N Technic 299 Technic 450 Techno Alpha 175

DTXSID4024305

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-57-5

PCHJSUWPFVWCPO-UHFFFAOYSA-N

Gold

AGC Micro Britecote Burnish Gold C.I. Pigment Metal 3 Colloidal gold Finesphere Gold W 011 Furuuchi 8560 Gold black Gold element Gold Flake Gold Leaf Keradec Palegold 5550 Perfect Gold Shell Gold Technic 504

DTXSID3064697

15663-27-1

DQLATGHUWYMOKM-UHFFFAOYSA-L

Cisplatin

Cis Platinum, diamminedichloro-, (SP-4-2)- Abiplatin Biocisplatinum Briplatin cis-DDP cis-Diaminedichloroplatinum cis-Diaminedichloroplatinum(II) cis-Diaminodichloroplatinum(II) cis-Diamminedichloroplatinum cis-Diamminedichloroplatinum(II) cis-Dichlorodiamineplatinum(II) cis-Dichlorodiammineplatinum cis-Dichlorodiammineplatinum(II) Cismaplat cis-Platin cisplatine cis-Platine cisplatino cis-Platinous diaminodichloride Cisplatinum cis-Platinum cis-Platinum diaminodichloride cis-Platinum II cis-Platinum(II) diaminodichloride cis-Platinum(II) diamminedichloride cis-Platinumdiamine dichloride cis-Platinumdiammine dichloride Cisplatyl Citoplatino Lederplatin lipoplatin Neoplatin NSC 119875 Platamine Platiblastin Platidiam Platinex Platinol Platinol AQ Platinoxan Platinum, diamminedichloro-, cis- Platistin Platosin SPI 077B103 cis-Dichlorodiamine platinum cis-Dichloro diaminoplatinum II

DTXSID4024983

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

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

DTXSID2024169

7440-47-3

VYZAMTAEIAYCRO-UHFFFAOYSA-N

Chromium

Alpaste RRA 030 Alpaste RRA 050 Chromium element Chromium metal

DTXSID3031022

7440-66-6

HCHKCACWOHOZIP-UHFFFAOYSA-N

Zinc

Zn Asarco L 15 C.I. Pigment Black 16 Merrillite NC-Zinc Rheinzink Stapa TE Zinc AT UF (metal) UN 1436 Zinc dust Zinc Dust 3 Zinc Dust 500 mesh Zinc Dust LS 2 Zinc Dust MCS Zinc Flakes GTT ZINC METAL ZINC MOSSY ZINC STRIP ZINC, MOSSY Zincsalt GTT

DTXSID7035012

7429-90-5

XAGFODPZIPBFFR-UHFFFAOYSA-N

AZDRQVAHHNSJOQ-UHFFFAOYSA-N

Aluminum

Aisin Metal Fiber Al 050P-H24 ALC Fine Alcan XI 1391 Almi-Paste SSP 303AR Aloxal 3010 Alpaste 00-0506 Alpaste 0100M Alpaste 0100MA Alpaste 0100M-C Alpaste 0200M Alpaste 0200T Alpaste 0230M Alpaste 0230T Alpaste 0241M Alpaste 0300M Alpaste 0500M Alpaste 0539X Alpaste 0620MS Alpaste 0625TS Alpaste 0638-70C Alpaste 0700M Alpaste 0780M Alpaste 0900M Alpaste 100M Alpaste 100MS Alpaste 100MSR Alpaste 1100M Alpaste 1100MA Alpaste 1100N Alpaste 1100NA Alpaste 1109MA Alpaste 1109MC Alpaste 1200M Alpaste 1200T Alpaste 1260MS Alpaste 1500MA Alpaste 1700NL Alpaste 1810YL Alpaste 1830YL Alpaste 1900M Alpaste 1900XS Alpaste 1950M Alpaste 1950N Alpaste 210N Alpaste 2172EA Alpaste 2173 Alpaste 240T Alpaste 241M Alpaste 417 Alpaste 46-046 Alpaste 4-621 Alpaste 4919 Alpaste 50-63 Alpaste 50-635 Alpaste 51-148B Alpaste 51-231 Alpaste 5205N Alpaste 5207N Alpaste 52-509 Alpaste 52-568 Alpaste 5301N Alpaste 5302N Alpaste 53-119 Alpaste 5422NS Alpaste 54-452 Alpaste 54-497 Alpaste 54-542 Alpaste 55-516 Alpaste 55-519 Alpaste 55-574 Alpaste 5620NS Alpaste 5630NS Alpaste 5640NS Alpaste 56-501 Alpaste 5650NS Alpaste 5653NS Alpaste 5654NS Alpaste 5680N Alpaste 5680NS Alpaste 60-600 Alpaste 60-760 Alpaste 60-768 Alpaste 62-356 Alpaste 6340NS Alpaste 6370NS Alpaste 6390NS Alpaste 640NS Alpaste 65-388 Alpaste 66NLB Alpaste 710N Alpaste 7130N Alpaste 7160N Alpaste 7160NS Alpaste 725N Alpaste 740NS Alpaste 7430NS Alpaste 7580NS Alpaste 7620NS Alpaste 7640NS Alpaste 7670M Alpaste 7670NS Alpaste 7675NS Alpaste 7679NS Alpaste 7680N Alpaste 7680NS Alpaste 76840NS Alpaste 7730N Alpaste 7770N Alpaste 7830N Alpaste 8004 Alpaste 8080N Alpaste 8260NAR Alpaste 891K Alpaste 91-0562 Alpaste 92-0592 Alpaste 93-0595 Alpaste 93-0647 Alpaste 94-2315 Alpaste 95-0570 Alpaste 96-0635 Alpaste 96-2104 Alpaste 97-0510 Alpaste 97-0534 Alpaste AW 520B Alpaste AW 612 Alpaste AW 9800 Alpaste F 795 Alpaste FM 7680K Alpaste FX 440 Alpaste FX 910 Alpaste FZ 0534 Alpaste FZU 40C Alpaste G Alpaste HR 8801 Alpaste HS 2 Alpaste J Alpaste K 9800 Alpaste MC 666 Alpaste MC 707 Alpaste MF 20 Alpaste MG 01 Alpaste MG 1000 Alpaste MG 1300 Alpaste MG 500 Alpaste MG 600 Alpaste MH 6601 Alpaste MH 8801 Alpaste MH 9901 Alpaste MR 7000 Alpaste MR 9000 Alpaste MS 630 Alpaste N 1700NL Alpaste NS 7670 Alpaste O 100N Alpaste O 2130 Alpaste O 300M Alpaste P 0100 Alpaste P 1950 Alpaste S Alpaste SAP 110 Alpaste SAP 414P Alpaste SAP 550N Alpaste SCR 5070 Alpaste TCR 2020 Alpaste TCR 2060 Alpaste TCR 2070 Alpaste TCR 3010 Alpaste TCR 3030 Alpaste TCR 3040 Alpaste TCR 3130 Alpaste TD 200T Alpaste UF 500 Alpaste WB 0230 Alpaste WD 500 Alpaste WJP-U 75C Alpaste WX 0630 Alpaste WX 7830 Alpaste WXA 7640 Alpaste WXM 0630 Alpaste WXM 0650 Alpaste WXM 0660 Alpaste WXM 1415 Alpaste WXM 1440 Alpaste WXM 5422 Alpaste WXM 760b Alpaste WXM 7640 Alpaste WXM 7675 Alpaste WXM-T 60B Alpaste WXM-U 75 Alpaste WXM-U 75C Altop X Aluchrome Ultrafin Super Alumat 1600 Alumet H 30 aluminio Aluminium Aluminium Flake Aluminum 27 Aluminum atom Aluminum element Aluminum Flake PCF 7620 Aluminum granules ALUMINUM METAL/GRANULE ALUMINUM PASTE ALUMINUM PIGMENT ALUMINUM TURNINGS Alumi-paste 640NS Alumipaste 91-0562 Alumipaste 98-1822T Alumipaste AW 620 Alumipaste CR 300 Alumipaste GX 180A Alumipaste GX 201A Alumipaste HR 7000 Alumipaste HR 850 Alumipaste MG 11 Alumipaste MH 8801 Aquamet NPW 2900 Aquapaste 205-5 Aquasilver LPW Astroflake 40 Astroflake Black N 020 Astroflake Black N 070 Astroflake LG 40 Astroflake LG 70 Astroflake Silver N 040 Astroshine NJ 1600 Astroshine T 8990 Atomizalumi VA 200 C.I. PIGMENT METAL 1 Chromal IV Chromal X Decomet 1001/10 Decomet 2018/10 Decomet High Gloss Al 1002/10 Ecka AS 081 Eckart 9155 Eterna Brite 301-1 Eterna Brite 601-1 Eterna Brite 651-1 Eterna Brite EBP 251PA Eterna Brite Primier 251PA Ferro FX 53-038 Friend Color F 500GR-W Friend Color F 500WT Friend Color F 700RE-W Friend Color F 701RE-W Hi Print 60T High Print 60T Hisparkle HS 2 Hydro Paste 8726 Hydrolac WHH 2153 Hydrolan 3560 Hydrolux Reflexal 100 Hydroshine WS 1001 JISA 51010P Kryal Z Lansford 243 LE Sheet 800 Leafing Alpaste LG-H Silver 25 Lunar Al-V 95 Metallux 161 Metallux 2154 Metallux 2192 Metalure Metalure 55350 Metalure L 55350 Metalure L 59510 Metalure W 2001 Metapor Metasheen 1800 Metasheen HR 0800 Metasheen KM 100 Metasheen KM 1000 Metasheen Slurry 1807 Metasheen Slurry 1811 Metasheen Slurry KM 100 Metax G Metax S Mirror Glow 1000 Mirror Glow 600 Mirrorsheen Noral Aluminium Noral Ink Grade Aluminium Obron 10890 Offset FM 4500 Puratronic Reflexal 145 Reynolds 400 Reynolds 4-301 Reynolds 4-591 Reynolds 667 SAP 260PW-HS SAP-FM 4010 SBC 516-20Z Scotchcal 7755SE Serumekku Setanium 50MIS-H8 Siberline ET 2025 Siberline ST 21030E1 Silvar A Silver VT 522 Silverline SSP 353 Silvex 793-20C Sparkle Silver 3141ST Sparkle Silver 3500 Sparkle Silver 3641 Sparkle Silver 5000AR Sparkle Silver 516AR Sparkle Silver 5242AR Sparkle Silver 5245AR Sparkle Silver 5271AR Sparkle Silver 5500 Sparkle Silver 5745 Sparkle Silver 7000AR Sparkle Silver 7005AR Sparkle Silver 7500 Sparkle Silver 960-25E1 Sparkle Silver E 1745AR Sparkle Silver L 1526AR Sparkle Silver Premier 751 Sparkle Silver SS 3130 Sparkle Silver SS 5242AR Sparkle Silver SS 5588 Sparkle Silver SSP 132AR Special PCR 507 Splendal 6001BG Spota Mobil 801 SSP 760-20C Stapa Aloxal PM 2010 Stapa Aloxal PM 3010 Stapa Aloxal PM 4010 Stapa Hydrolac BG 8n.1 Stapa Hydrolac BGH Chromal X Stapa Hydrolac PM Chromal VIII Stapa Hydrolac W 60NL Stapa Hydrolac WH 16 Stapa Hydrolac WH 66NL Stapa Hydrolux 2192 Stapa Hydrolux 8154 Stapa IL Hydrolan 2192-55900G Stapa Metallic R 607 Stapa Metallux 1050 Stapa Metallux 211 Stapa Metallux 212 Stapa Metallux 2196 Stapa Metallux 274 Stapa Mobilux 181 Stapa Offset 3000 Stapa PV 10 Stapa VP 46432G Starbrite 2100 Super Fine 18000 Super Fine 22000 Supramex 2022 Toyo Aluminum 02-0005 Toyo Aluminum 93-3040 Transmet K 102HE Tufflake 3645 Tufflake 5843 UN 1396 US Aluminum 809 Valimet H 2 Valimet H 3 White Silver 7080N White Silver 7130N

DTXSID3040273

GO:0005764

GO lysosome

CL:1000507

CL kidney tubule cell

UBERON:0002113

UBERON kidney

GO:1903008

GO organelle disassembly

GO:0008219

GO cell death

Q000633

MESH toxicity

WIKI functional change

WIKI occurrence

WIKI increased

Aminoglycosides

2017-10-25T08:29:51

Gentamicin

2017-10-25T08:30:15

Tobramycin

2017-10-25T08:30:48

Vancomycin

2017-10-25T08:31:08

Polymyxin B

2017-10-25T08:31:35

Colistin

2017-10-25T08:31:49

Albumin

2017-10-25T08:32:07

low molecular weight proteins

2017-10-25T08:32:47

Cadmium

2017-10-25T08:33:12

Mercury

2016-11-29T18:42:19

Uranium

2021-08-05T14:28:50

Silver

2022-02-03T11:20:11

Arsenic

2021-04-27T00:15:21

Gold

2022-02-07T15:25:56

Nanoparticles and Micrometer Particles

2022-02-04T13:43:43

Cisplatin

2022-02-03T11:34:57

Manganese

2022-02-04T14:47:23

Chromium

2022-02-03T11:22:01

Zinc

2022-02-04T15:05:00

Aluminum

2022-02-04T14:42:11

WCS_9606

common toxicological species human

10090

NCBI mouse

WikiUser_15

ApacheUser Sprague-Dawley

WikiUser_4

Wikiuser: Blandesmann Human, rat, mouse

WCS_9615

common toxicological species dog

WikiUser_14

Wikiuser: Ftschudi Monkey

Binding of substrate, endocytic receptor

Molecular

AOPWiki 2017-10-25T08:40:47

2017-10-25T08:49:47

Disturbance, Lysosomal function

Cellular

CL:0000255

CL eukaryotic cell

AOPWiki 2016-11-29T18:41:27

2017-09-16T10:16:33

Disruption, Lysosome

Cellular

Lysosomes were first described in 1955 (de Duve et al., 1955). They are acidic, single-membrane bound organelles that are present in all eukaryotic cells and are filled with more than 50 acid hydrolases to serve their purpose of degrading macromolecules (Johansson et al., 2010). Lysosomes are the terminal organelle of the endocytic pathway, but are also involved in membrane repair and other cellular processes, such as immune responses (Repnik and Turk, 2010). There are numerous substances that can provoke increased permeability of lysosomal membrane or total lysosomal rupture, and as a consequence release of lysosomal enzymes. Among lysosomal enzymes, one of the major roles has cathepins. There are 11 cysteine cathepins in humans, B, C, F, H, K, L, O, S, V, W and X. Activation of proenzymes usually occurs within the lysosomes (Ishidoh and Kominami, 2002), therefore, the enzymes escaping from the lysosomes are in their active form. The amount of lysosomal enzymes that are released into the cytosol regulates the cell death pathway which is initiated by lysosomal damage: controlled increased permeability of lysosomal membrane, caused by limited level of stress, plays a vital role in the induction of apoptosis, whereas massive lysosomal rupture, caused by high stress levels, leads to necrosis (Bursch, 2001; Guicciardi et al., 2004). Lysosomes are known to be involved in external as well as internal apoptotic pathways. The external pathway triggers lysosomal destabilization by hydroxyl radicals, p53, and caspase 8, through activation of Bax or by ceramide which is converted into sphingosine (Terman et al., 2004). The internal apoptotic pathway on the contrary is activated through mitochondrial damage, for example via activation of Bax or Bid, phospholipases, or lysosomal enzymes (Terman et al., 2004). It has been shown that lack of cathepsin B prevents increased lysosomal membrane permeability in hepatocytes treated with TNF or sphingosine (Werneburg et al., 2002). This indicates that cathepsins can also have a role in initiation of increased lysosomal membrane permeabilization. The lysosome contains redox-active labile irons which are suggested to be involved in local ROS production via a Fenton-type reaction (Kubota et al., 2010). It has been shown that lysosomal membrane disruption induced by lysosomotropic detergents causes early induction of lysosomal cathepsin B and D and induction of ferritin, together with an increase of cellular ROS and concomitant reduction of the antioxidants MnSOD (manganese superoxide dismutase) and GSH (glutathione), possibly due to the release of free iron into the cytosol (Ghosh et al., 2011; Hamacher-Brady et al., 2011). The list of agents able to destabilize lysosomal membrane includes L-Leucyl-L-leucinemethyl ester (LLOMe) (Goldman and Kaplan, 1973; Uchimoto et al. 1999; Droga-Mazovec et al., 2008),  N-dodecylimidazole (NDI) (Wilson et al., 1987), sphingosine (Kagedal et al., 2001), detergent MSDH (Li et al., 2000), siramesine (Ostenfeld et al., 2005), the quinolone antibiotics ciprofloxacin and norfloxacin (Boya et al., 2003a),  hydroxychloroquine (Boya et al., 2003b) and NPs (Wang et al., 2018). Cirman et al. showed that the lysosomotropic agent LLOMe inducing the disruption of lysosomes results in translocation of lysosomal proteases to the cytosol and induce apoptosis through a caspase dependent mechanism (Cirman et al., 2004). However, it has been proven that partially increased permeabilization of lysosome leads to apoptosis, while complete breakdown of the lysosome with release of high concentrations of the enzymes into the cytosol results in necrosis (Bursch, 2001; Kurz et al., 2008). The short-term exposure to low concentrations of H2O2 induce lysosomal rupture by activation of phospholipase A2, which cause a progressive destabilization of the membranes of intracellular organelles degrading the membrane phospholipids (Zhao et al., 2001). Sumoza-Toledo and Penner showed that ROS activate lysosomal Ca2+ channels and contribute to increased lysosomal permeability (Sumoza-Toledo and Penner, 2011).   Considering nanomaterials (NMs) as a trigger for lysosomal damage, recent studies underpinned the importance of lysosomal NM uptake for NM-induced toxicity. Once the material is taken up by a cell and transported to the lysosome by autophagy, the acidic milieu herein can either enhance solubility of a NM, or the material remains in its initial nano form. Both situations can induce toxicity, causing lysosomal swelling, followed by lysosomal disruption and the release of pro-apoptotic proteins (Wang et al., 2013; Cho et al., 2011; Cho et al., 2012). Wang et al. showed that the exposure of cells to NH2-PS NPs results in increased lysosomal membrane permeability and release of lysosomal proteasis (cathepsin B and cathepsin D) into cytosol (Wang et al., 2018).

Lysosomes are typically analysed microscopically, usually with fluorescence microscopy (Kagedal et al., 2001).   Changes in morphology can be observed by using acridine orange (AO), a weak base that accumulates in the acidic compartment of the cell mainly composed of lysosomes. Red fluorescence is exhibited when it is highly concentrated in acidic vesicles, while green fluorescence is exhibited when it's less concentrated in other parts of the cell (Li et al., 2000; Reiners et al., 2002; Kroemer and Jäättelä, 2005). This is followed by flow cytometry (Zhao et al., 2001), static cytofluometry or flow cytofluometry (Antunes et al., 2001). Lysotracker green (200 nM) is regularly used to assess lysosomal acidification; Anguissola and colleagues reported that it was excited through a 475+/240 nm band pass filter and fluorescence emission was collected through a 515+/220 nm band pass filter. Analysis is performed using microscopical methods such as High Content Analysis (Anguissola et al., 2014). This method as well as use of LysoSensor probes has been reported repeatedly elsewhere, for example (Wang et al., 2013; Kroemer and Jäättelä, 2005).  More specific staining can be achieved by staining with antibodies against lysosomal membrane proteins (Kroemer and Jäättelä, 2005).  Lysosomal membrane permeabilization can be visualized by immunostaining of lysosomal enzymes such as cathepsin B (Boya et al. 2003a).

Typically, human or murine cell lines are used to assess this event. Examples are  murine (Reiners et al., 2002) murine, human (Li et al., 2000) murine, human (Ghosh et al., 2011) human (Loos et al., 2014) human, murine (Anguissola et al., 2014) human (Hamacher-Brady et al., 2011)

Not Specified Unspecific

Not Specified

All life stages

High High

Anguissola S, Garry D, Salvati A, O'Brien PJ, Dawson KA. High content analysis provides mechanistic insights on the pathways of toxicity induced by amine-modified polystyrene nanoparticles. PLoS One. (2014) 9(9):e108025. Antunes F, Cadenas E, Brunk UT. Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture. Biochemical Journal. (2001) 356(Pt 2):549-555. Boya P,  Andreau K, Poncet D,  Zamzami N, Perfettini JL, Metivier D, Ojcius DM,  Jäättelä M, Kroemer G. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion, J. Exp. Med. (2003) 197:1323–1334. Boya P, Gonzalez-Polo RA, Poncet D,  Andreau K, Vieira HL,  Roumier T, Perfettini JL, Kroemer G. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine, Oncogene (2003) 22:3927–3936. Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. (2001) 8(6):569-81. Cho W-S, Duffin R, Howie SEM, Scotton CJ, Wallace WAH, Macnee W, Bradley M, Megson IL, Donaldson K. Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part Fibre Toxicol (2011) 8:27. Cho W-S, Duffin R, Thielbeer F, Bradley M, Megson IL, MacNee W, Poland CA, Tran CL, Donaldson K. Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles. Toxicol Sci (2012) 126:469–477. Cirman T, Oresić K, Droga-Mazovec G, Turk V, Reed JC, Myers RM, Salvesen GS, Turk B. Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins. J Biol Chem. (2004) 279(5): 3578–3587. de Duve C, Pressman BC, Gianetto R, Wattiaux R, Applemans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. (1955) 60(4):604-17. Droga-Mazovec G, Bojič L, Petelin A, Ivanova S, Romih R, Repnik U, Salvesen GS, Stoka V, Turk V, Turk B. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues, J. Biol. Chem. (2008) 283:19140–19150. Ghosh M, Carlsson F, Laskar A, Yuan XM, Li W. Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages. FEBS Lett. (2011) 585(4):623-9. Goldman R, Kaplan A. Rupture of rat liver lysosomes mediated by L-amino acid esters, Biochim. Biophys. Acta  1973, 318: 205–216. Guicciardi ME, Leist M, Gores GJ. Lysosomes in cell death. Oncogene. (2004) 23(16):2881-90. Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R, Brady NR. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. (2011) 286(8):6587-601. Ishidoh K, Kominami E. Processing and activation of lysosomal proteinases. Biol Chem. (2002)  383(12): 1827–1831. Johansson AC, Appelqvist H, Nilsson C, Kågedal K, Roberg K, Ollinger K. Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis. (2010) 15(5):527-40. Kagedal K, Zhao M, Svensson I, Brunk UT. Sphingosine-induced apoptosis is dependent on lysosomal proteases. The Biochemical journal.  (2001) 359:335-43. Kroemer G, Jäättelä M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. (2005) 5(11):886-97. Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem. (2010) 285(1):667-74. Kurz T, Terman A, Gustafsson B, Brunk  UT.  Lysosomes in iron metabolism, ageing and apoptosis. Histochem. Cell Biol. (2008) 129: 389-406. Li W, Yuan X, Nordgren G, Dalen H, Dubowchik GM, Firestone RA, Brunk UT. Induction of cell death by the lysosomotropic detergent MSDH, FEBS Lett. (2000) 470:35–39. Loos C, Syrovets T, Musyanovych A, Mailänder V, Landfester K, Nienhaus GU, Simmet T. Functionalized polystyrene nanoparticles as a platform for studying bio-nano interactions. Beilstein J Nanotechnol. (2014) 5:2403-12. Ostenfeld MS, Fehrenbacher N, Høyer-Hansen M, Thomsen C,  Farkas T,  Jäättelä M. Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress, Cancer Res. (2005) 65:8975–8983. Reiners J, Caruso J, Mathieu P, Chelladurai B, Yin X-M, Kessel D. Release of cytochrome c and activation of pro-caspase-9 following lysosomal photodamage involves bid cleavage. Cell death and differentiation. (2002) 9(9):934-944. Repnik U, Turk B. Lysosomal-mitochondrial cross-talk during cell death. Mitochondrion. (2010) 10(6):662-9. Sumoza-Toledo A, Penner R. TRPM2: a multifunctional ion channel for calcium signalling. J. Physiol. (2011) 589:1515-1525. Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal. (2010) 12(4):503-35. Uchimoto T, Nohara H, Kamehara R, Iwamura M, Watanabe N, Kobayashi Y. Mechanism of apoptosis induced by a lysosomotropic agent, L-Leucyl-L-Leucine methyl ester, Apoptosis (1999) 4:357–362. Wang F, Bexiga MG, Anguissola S, Boya P, Simpson JC, Salvati A, Dawson KA: Time resolved study of cell death mechanisms induced by amine-modified polystyrene nanoparticles. Nanoscale (2013) 5:10868–76. Wang F, Salvati A, Boya P. Lysosome-dependent cell death and deregulated autophagy induced by amine-modified polystyrene nanoparticles. Open Biol. (2018) 8(4): 170271. Werneburg NW, Guicciardi ME, Bronk SF, Gores GJ. Tumor necrosis factor-alpha-associated lysosomal permeabilization is cathepsin B dependent. Am J Physiol Gastrointest Liver Physiol. (2002) 283:G947–G956. Wilson PD, Firestone RA, Lenard J. The role of lysosomal enzymes in killing of mammalian cells by the lysosomotropic detergent N-dodecylimidazole, J. Cell. Biol. (1987) 104:1223–1229. Zhao M, Brunk UT, Eaton JW. Delayed oxidant-induced cell death involves activation of phospholipase A2. FEBS Lett. (2001) 509:399–404. Zhao M, Eaton JW,  Brunk UT. Bcl-2 phosphorylation is required for inhibition of oxidative stress induced lysosomal leak and ensuing apoptosis. FEBS Lett. (2001) 509: 405–412.   AOPWiki 2016-11-29T18:41:27

2018-11-12T08:23:19

Increase, Cytotoxicity (renal tubular cell)

Cellular

The renal proximal tubule is a crucial section of the nephron, responsible for the bulk of its reabsorption capabilities. About 60-70% of glomerular filtrate such as water, small molecules, and important ions, as well as nearly all the filtered amino acids, small peptides, and glucose are reabsorbed in the proximal tubule (Carson, 2019). The process of solute reabsorption is highly energetically expensive, making the proximal tubules the renal region of highest oxygen consumption. The microvilli, densely packed to form the brush border apical surface of the tubules, have abundant elongated mitochondria to sustain the energetic demand of their function (Carlson, 2019). The introduction of heavy metals into the kidneys causes aggregation in the proximal tubules due to their high mitochondrial content, leading to inhibition of the electron transport chain and reactive oxygen species (ROS) production. This area is particularly susceptible to heavy metal toxicity due to the abundance of mitochondria, as well as the fact that, regardless of toxicity, approximately 70% of cation absorption and transport passes through the proximal tubules (Barbier et al., 2005). Some heavy metal transport into the proximal tubules is conducted by MRP-1 and MRP-2 (ATP binding cassette-multidrug resistance proteins), and characterize toxicity by GSH depletion as some metals such as arsenic bind GSH and increased oxidative stress induced by free radicals (Sabath & Robles-Osorio, 2012). This oxidative stress causes disruption to mitochondrial homeostasis and mitophagy in proximal tubular epithelial cells by altering PPAR (peroxisome proliferator-activated receptor) (Small et al., 2018). At high enough concentrations of toxic heavy metals they can lead to cytotoxicity and cell death. An issue with assessment of kidney function is that the kidneys notoriously compensate for loss of function, leading to the appearance of adverse affects only at a late onset when there is very severe levels of damage (de Burbure et al., 2003). Cell Death and Cytotoxicity Cell death is a variety of processes defined by a cell ceasing to perform its function. This could happen by a variety of mechanisms. Apoptosis is a programmed physiological sequence leading to controlled cell death deemed necessary for the fitness and survival of the organism (cell is redundant, dysfunctional, cancerous, etc.) (Choi et al., 2019). Apoptosis, in the case of DNA damage, can be induced by free radicals produced as a result of heavy metal exposure, as shown in ex-vivo studies (Miller et al., 2002). Another cause by heavy metal exposure is physical and structural damage to mitochondria, damaging cellular metabolism and ATP production. There are many possible stressors that may lead to cell death, the effects exhibited depend on the cell type and the severity of the stress (Liu et al., 2018). Some modes of cell death include: apoptosis (programmed cell death), necrosis (uncontrolled cell death), and aging-caused cell death, known as senescent death  (Liu et al., 2018). <div>Apoptosis, also referred to as programmed cell death, is the predetermined procedure by which an organism disposes of cells that are no longer productive (Liu et al., 2018; Elmore, 2007). Apoptosis biochemically  manifests as cytoplasmic shrinkage, cytoskeleton collapse, chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis), mitochondrial dysfunction, cytochrome c release, altered Bcl-2 family protein expression or activation, plasma membrane blebbing, and in larger cells, the formation of apoptotic bodies. The surface of cells undergoing apoptosis is chemically altered to signal nearby cells and macrophages that then rapidly engulf them before they spill their contents (Alberts et al., 2014; Choi et al., 2019). Apoptosis occurs in three general phases: initiation, effector, and final. Variation can be seen as the initiation phase is dependant on stimuli, and there are two effector phase modes; an extrinsic and intrinsic pathways. Regardless of the pathway of the first 2 phases, the final stage of apoptosis is caspase-3 activation (Priant et al., 2019). The initiation and execution of apoptosis and other cell death processes is induced by the proteolytic activity of caspase as it cleaves the aspartic acid residues of proteins. The caspases can be broadly divided into two groups: those that are mainly involved in apoptosis (caspase-2, -3, -6, -7, -8, -9, and -10) and those related to caspase-1, whose primary role appears to be cytokine processing and pro-inflammatory cell death (caspase-1, -4, -5, -11, -12, -13, and -14). The apoptotic caspases can further be divided into initiator caspases (caspase-2, -8, -9, and -10) and executioner caspases (caspase-3, -6, and-7) (Fink & Cookson, 2005). Once the initial caspase activation occurs the resultant caspase cascade is irreversible (Alberts et al., 2014).</div> <div> </div> The extrinsic pathway, also known as the death receptor-mediated pathway, involves the ligation of death receptors determining the activation of caspase-8. Caspase-8 further activates downstream caspases leading to apoptosis (Priante et al., 2019). This pathway is triggered by extracellular signalling proteins binding to cell-surface death receptors. A well understood example of this process is the activation of the Fas receptor on the surface of a target cell by Fas ligand (FasL) on the surface of a cytotoxic lymphocyte (Alberts et al., 2014). In this process, the cytosolic Fas death receptor binds intracellular adaptor proteins. This complex then binds initiator, caspases, primarily caspase-8, forming a death-inducing signalling complex (DISC). The initiator caspases, once dimerized and activated in the DISC, activate downstream executioner caspases to induce apoptosis (Nair et al., 2014). In some cells, the extrinsic pathway recruits the intrinsic apoptotic pathway to amplify the caspase cascade. These pathways are linked by caspase-8, that triggers the caspase cascade and the protein, Bid (Priante et al., 2019; Alberts et al., 2014). Type I cells act independent of mitochondria for the induction of Fas death receptor-mediated apoptosis, and have therefore optimized the extrinsic pathway. Thymocytes or cells responsible for the immune system in general, for example, are expected to signal each other or target cells through membrane bound ligands, like FasL and TRAIL (Ozoren and El-Deiry, 2002). The intrinsic pathway is often referred to as the mitochondrial pathway of apoptosis. Pro-apoptotic Bcl-2 family proteins, Bax and Bak, create pores on the outer mitochondrial membrane, determining the release of apoptogenic factors, such as cytochrome c. In the cytosol, cytochrome c binds to, and stimulates, conformational modifications in the adaptor protein, Apaf-1, thus leading to the enrolment and activation of caspase-9. Caspase-9 further activates executioner caspases to elicit apoptosis (Priante et al., 2019). Type II cells are mitochondria-dependent, where the mitochondria are crucial to ensure successful apoptosis. For example, liver and kidney cells are responsible for the detoxification of the blood from chemicals toxicants, many of which are cytotoxic and genotoxic agents known to predominantly activate the intrinsic pathway (Ozoren and El-Deiry, 2002). In a study conducted by Eichler et al. (2006), cultured murine podocytes were incubated for three days with arsenite, cadmiuim, or mercury, as well as an equimolar combination of the three to test the modes and extent of apoptosis induced by the exposure. It was seen that the mix of metal exposure showed significantly fewer apoptotic affects, indicating an antagonistic affect of the metals over an additive or synergistic toxicity. It was also seen that the apoptosis observed in the separate metal tests showed a ~400% increase of caspase 8 activity as well as ~500% upregulation of Fas, factors of the extrinsic pathway. No significant change was seen to the intrinsic pathway factors. The results of this experiment indicate that heavy metals favour extrinsic apoptosis as their method of cytotoxicity. Necrosis is characterized as passive, accidental cell death resulting from environmental perturbation with uncontrolled release of inflammatory cellular contents (Fink & Cookson, 2005). Contrastingly, apoptosis is an active, intentional, programmed process of autonomous cellular dismantling that avoids eliciting inflammation. These modes would then be categorized into Accidental Cell Death (ACD) and Regulated Cell Death (RCD), respectively fitting necrosis and apoptosis (Choi et al., 2019). Necrosis biochemically manifests through plasma membrane rupture, cell swelling and lysis, energy decline, DAMP release, and emptying of cell contents (Choi et al., 2019; Thiebault et al., 2007). The caspases governing inflammatory cell death, such as necrosis, are caspases-1, -4, -5, -11, -12, -13, and -14 (Fink and Cookson, 2005). Cell fate could be decided by a number of factors. For instance, ATP is required for the execution of apoptosis, so, when lacking, apoptosis is disabled, making the mode of cell death ATP dependent (Shaki et al., 2012). Between apoptosis and necroptosis, cell fate is influenced primarily by the availability of caspase-8 and the cellular or X-linked inhibitors of apoptosis proteins (cIAP1, cIAP2, XIAP). Thiebault et al. (2007) studied the mechanism of cell mortality induced by uranium in NRK-52E cells and found that after low exposure to uranium (below the CI50 concentration, 500µL), apoptotic cell death was observed, whereas higher exposure to uranium resulted in necrotic cell death. Multiple types of death can be observed simultaneously in tissues exposed to the same stimulus, and the local intensity of a particular stimulus may influence the cell death mechanism (Fink and Cookson, 2005).

<table border="1" cellpadding="1" cellspacing="1"> <tbody> <tr> <td>Assay Type & Measured Content</td> <td>Description</td> <td>Dose Range Studied</td> <td> Assay Characteristics (Length/Ease of use/Accuracy)</td> </tr> <tr> <td> Kidney function assay Measuring total urinary protein, albumin, transferrin, b2-microglobulin, retinolbinding protein, brush border tubular antigens, N-acetyl-b-Dglucosaminidase activity, serum and urinary creatine   (de Burbure et al., 2003)</td> <td>“All analyses of a given parameter were performed under similar experimental conditions in the same laboratories within 6mo of collection. Total urinary protein (Prot-T-U) was determined by the Coomassie blue G250 binding method. Albumin (Alb-U), transferrin (Transf-U), β2-microglobulin (β2m-U), and retinolbinding protein (RBP-U) in urine were quantified by latex immunoassay (Bernard & Lauwerys, 1983). Acceptable limits for precision and accuracy of measurements and external quality controls were the same as those described in the Cadmibel study (Lauwerys et al., 1990). The brush border tubular antigens (BBA-U) were analyzed by a sandwich enzyme-linked immunoassay using monoclonal antibodies (Mutti et al., 1985). The total activity of N-acetyl-β-Dglucosaminidase (NAG-T-U) in urine was determined colorimetrically using a kit (PPR Diagnostics Ltd.) as described elsewhere (Price et al., 1996). Only total NAG (NAG-T) was used for the purpose of this study. Serum and urinary creatinine (Creat-U) were measured by the methods of Heinegard and Tiderström (1973), and Jaffé, respectively (Henry, 1965).” (de Burbure et al., 2003)</td> <td>“The soil contamination in the area varied from 100 to 1700ppm lead (with values higher than 1000ppm in the immediate vicinity of the factories), 0.7 to 233ppm cadmium, and 101 to 22,257ppm zinc, with the highest concentrations being recorded within 500 m of the 2 factories”</td> <td> </td> </tr> <tr> <td> N-ACETYL-b-D-GLUCOSAMINIDASE (NAG) ASSAY Measuring NAG urinary content (Lim et al., 2016)</td> <td>“Urinary NAG activity was measured by using NAG Quantitative Kit (Shionogi, Osaka, Japan). After storing a synthetic substrate solution (1 mL) at 37°C for five minutes, the solution was mixed with the supernatant of the urine samples (50 mL) received after centrifugation. After storing it at 37°C for 15 min, stopping solution (2 mL) was added to and mixed with it. By using a spectrophotometer, its fluorescence intensities were measured with a wavelength of 580 nm (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057">13</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057">14</a>). Urinary β2-MG was measured by using Enzygnost β2-MG Micro Kit (Behring Institute, Mannheim, Germany). Its method used the principle of solid phase enzyme-linked immunosorbent assay (ELISA). Monoclonal anti-β2-MG antibody and anti-2-MG-horseradish peroxidase conjugate solution were used. After that, color intensities were measured with a wavelength of 450 nm by using a spectrophotometer (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057">13</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057">14</a>).” (Lim et al., 2016)</td> <td>Cd & Pb</td> <td>Fast, easy, accurate</td> </tr> <tr> <td> MTT Assay (cytotoxicity) Measuring Cell Viability (Thiebault et al., 2007; Shaki et al., 2012)</td> <td>This assay is a quantitative and sensitive method of detection of cell proliferation, measuring the growth rate of cells via activity and absorbance. It relies on the reduction of MTT (yellow, water-soluble tetrazolium dye) by mitochondrial dehydrogenases, to purple colored formazan crystals. The samples are then analyzed via spectrophotometry (550 nm). This assay can also be used to asses electron transport function.</td> <td> 50, 100 and 500 μM of uranyl acetate; 0-1000µM U</td> <td> Long Easy/Difficult High accuracy (mathematical measurement) Medium Precision</td> </tr> <tr> <td> LDH Cytotoxicity Assay Measuring Necrosis via Lactate Dehydrogenase release (Thiebault et al., 2007)</td> <td>LDH is released into extracellular space when the plasma membrane is damaged. To detect the leakage of LDH into cell culture medium as a measurement of membrane integrity, a tetrazolium salt is used in this assay. LDH oxidizes lactate to generate NADH, which then reacts with WST to generate a yellow colour. LDH activity can then be quantified by spectrophotometer or plate reader. </td> <td>15, 30 µM Cd</td> <td>Fast, easy, high accuracy</td> </tr> <tr> <td> Caspase-3 and -8 colorimetric assay, Caspase-9 fluoresceine assay Measuring apoptosis initiation and execution via caspases 3, 8, 9 activity (Thiebault et al., 2007)</td> <td>After cell lysate centrifugation, 10 µL of the supernatant was incubated with 80 µL of the caspase assay buffer and 10 µL of the colorimetric caspase-3 (Acetyl-asp-glu-val-asp-p-nitroanilide) or caspase-8 (Acetyl-ile-glu-thr-asp-p-nitroaniline) substrate. Plates were incubated for 90 min at 37° C and absorbance was read at 405 nm with a Statfax-2100 microplate reader. Fluorescence intensity of cell suspensions measuring caspase-9 activity was measured at an excitation wavelength of 490 nm and an emission wavelength of 530 nm with fluorescence spectrophotometer.</td> <td>0-800µM U</td> <td>Long, difficult, high accuracy</td> </tr> </tbody> </table> “Techniques such as micropuncture, microinjection [1, 6, 18] and microperfusion of isolated tubules [14] have made it possible to map the reabsorption of the heavy metals along the different segments of the nephron.” (Barbier et al., 2005) “Pb2+ , Hg2+ induced glomerular and tubular damage characterized by a reduced GFR, glycosuria, proteinuria and a rapid obstruction of the tubular system [13]” (Barbier et al., 2005) “Concerning chronic intoxication, most heavy metals (Cd2+ , Hg2+ , Pb2+ ) induced a Fanconi syndrome characterized by a decrease of the GFR, an increase in urinary flow rate, proteinuria, glycosuria, aminoaciduria and excessive loss of major ions.” (Barbier et al., 2005) “In the proximal tubule, Cd2+ has been shown to decrease phosphate and glucose transport by inhibiting the NaPi and the Na/glucose cotransporters respectively.” (Barbier et al., 2005) “In the kidney, Cd mainly affects PCT cells. This damage manifests clinically as low molecular weight proteinuria, aminoaciduria, bicarbonaturia, glycosuria and phosphaturia. Tubular damage markers such as alpha-1-microglobulin, beta-2-microglobulin, NAG and KIM-1 (kidney injury molecule-1) are useful in detecting early tubular damage.” (Sabath & Robles-Osorio, 2012)

All animals with kidneys containing renal proximal tubules.

CL:1000507

CL kidney tubule cell

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/" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK21054/</a> Barbier, O., Jcquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the  kidney. Nephron Physiology, 99, 105-110. doi:10.1159/000083981 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. The scientific world, 2012, 1-14. doi:10.1100/2012/136063 Carlson, B. M. (2019). The urinary system. The Human Body Academic Press, , 357-372. doi:https://doi.org/10.1016/B978-0-12-804254-0.00013-2 Choi, M. E., Price, D. R., Ryter, S. W., & Choi, A. M. K. (2019). Necroptosis: A crucial pathogenic mediator of human disease. JCI Insight, 4(15), 1-16. doi:10.1172/jci.insight.128834 Chomchan, R., Siripongvutikorn, S., Malyam, P., Saibandith, B., & Puttarak, P. (2018). Protective effect of selenium-enriched ricegrass juice against cadmium-induced toxicity and DNA damage in HEK293 kidney cells. Foods, 7, 81. doi:10.3390/foods7060081 De Burbure , C., Buchet , J., Bernard , A., Leroyer , A., Nisse , C., Haguenoer , J., Bergamaschi E., & Mutti, A. (2003). Biomarkers of Renal Effects in Children and Adults with Low Environmental Exposure to Heavy Metals. Journal of Toxicology and Environmental Health Part A, 66:9, 783-798, DOI: 10.1080/15287390306384 Fink, S. L., & Cookson, B. T. (2005). Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells. Infection and Immunity, 73(4), 1907-1916. doi:73/4/1907 [pii] Guéguen, Y., Suhard, D., Poisson, C., Manens, L., Elie, C., Landon, G., . . . Tessier, C. (2015). Low-concentration uranium enters the HepG2 cell nucleus rapidly and induces cell stress response. Toxicology in Vitro, 30, 552-560. doi:10.1016/j.tiv.2015.09.004 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 Hinkle, P. M., Kinsella, P. A., & Osterhoudt, K. C. (1987). Cadmium uptake and toxicity via voltage-sensitive calcium channels. Journal of Biological Chemistry, 262(34), 16333-16337. Karlsson, H. L., Gustafsson, J., Cronholm, P., & Möller, L. (2009). 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Depleted uranium-catalyzed oxidative DNA damage: Absence of significant alpha particle decay. Journal of Inorganic Biochemistry, 91(1), 246-252. doi:10.1016/S0162-0134(02)00391-4 Miyayama, T., Arai, Y., Suzuki, N., & Hirano, S. (2013). Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells follwoing exposure to silver nitrate. Toxicology, 305, 20-29. doi:10.1016/j.tox.2013.01.004 Muller, D., Houpert, P., Cambar, J., & Henge-Napoli, M. (2006). Role of the sodium-dependent phosphate co-transporters and of the phosphate complexes of uranyl in the cytotoxicity of uranium in LLC-PK1 cells. Toxicology and Applied Pharmacology, 214, 166-177. doi:10.1016/j.taap.2005.12.016 Mezynska, M., Brzoska, M. M., Rogalska, J., & Galicka, A. (2019). 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On the toxicity and transportation mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent. Metallomics, 9, 1786. doi:10.1039/c7mt00271h Tad Eichler, Qing Ma, Caitlin Kelly, Jaya Mishra, Samir Parikh, Richard F. Ransom, Prasad Devarajan, William E. Smoyer, Single and Combination Toxic Metal Exposures Induce Apoptosis in Cultured Murine Podocytes Exclusively via the Extrinsic Caspase 8 Pathway, Toxicological Sciences, Volume 90, Issue 2, April 2006, Pages 392–399, <a href="https://doi.org/10.1093/toxsci/kfj106">https://doi.org/10.1093/toxsci/kfj106</a>Elmore, S. (2007). Apoptosis: A review of programmed cell death. Toxicologic Pathology, 35(4), 495-516. doi:779478428 [pii] Thiébault, C., Carrière, M., Milgram, S., Simon, A., Avoscan, L., & Gouget, B. (2007). Uranium induces apoptosis and is genotoxic to normal rat kidney (NRK-52E) proximal cells. Toxicological Sciences : An Official Journal of the Society of Toxicology, 98(2), 479-487. doi:kfm130 [pii] Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biological Trace Element Research, 189, 95-108. doi:10.1007/s12011-018-1443-6 Yu, L., Li, W., Chu, J., Chen, C., Li, X., Tang, W., . . . Xiong, Z. (2021). Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase. Environmental Pollution, 271, 116377. doi:10.1016/j.envpol.2020.116377 Zhang, H., Chang, Z., Mehmood, K., Abbas, R. Z., Nabi, F., Rehman, M. U., . . . Zhou, D. (2018). Nano copper induces apoptosis in PK-15 cells via a mitochondria-mediated pathway. Biological Trace Element Research, 181(1), 62-70. doi:10.1007/s12011-017-1024-0   AOPWiki 2016-11-29T18:41:26

2022-03-03T15:14:42

Occurrence, Kidney toxicity

Organ

The kidneys are a crucial site of regulation of divalent cation levels in the plasma through filtration, reabsorption, and concentration (cite). On top of their excretion capabilities, the kidneys are also responsible for the production of hormones crucial for hematologic, cardiovascular, and skeletal muscle homeostasis (Bonventre et al., 2010). Nephrons are the functional units of the kidney and each kidney is made up of approximately 1 million nephrons (Bonventre et al., 2010). The nephrons are vital in reabsorption of these cations where 70% of transport has been shown to occur in the proximal tubule (Barbier et al., 2005). The kidneys are thought to be very susceptible to toxicity due to the increased concentration through their filtering structures with the tubular uptake mechanisms, specifically those of the proximal tubule, magnifying intracellular concentrations (Bonventre et al., 2010; Weber et al., 2017). Commonly, biomarkers like serum creatinine (sCr) and blood urea nitrogen (BUN) are utilized to identify kidney toxicity; however, these markers have been identified as nonspecific to the area of the kidney and slow in identification. Bonventre et al. (2010) has explored other biomarkers that may be used to identify segment specific injury. Proximal tubule injury can be identified using: albumin, RPB, NAG, clusterin, osteopontin, a1-microglobulin, and many others. Glomerulus damage can be identified through urinary Cystatin C, b2-microglobulin, a1-microglobulin, albumin, and more (Bonventre et al., 2010). These biomarkers do show some overlap between regions and can indicate damage to various areas of the nephron, though it is important to note the development of these specific techniques and therefore, the ability to develop more tailored and earlier identifying testing procedures. Since there are many essential metals for cellular function, there are also many transporters responsible for facilitating ionic entry into the cell and the designated cellular compartment (cite). Some of these transporters are very specific to a given metal and some are more diverse in the metals they handle, therefore, these transporters can facilitate the transport of toxic metals into the cell, often through mimickery exhibited by those metals (Ballatori, 2002). DMT1 (divalent metal transporter 1) is a strong example of such transporters. The introduction of toxic divalent cations (Cd2+, Pb2+, Pt2+, etc.) is highly problematic in the kidneys due to increased toxicity and occupancy of DMT1 limiting the transport of essential trace elements. DMT1 is an essential transport molecule that is highly expressed in the kidneys, and is responsible for transport of essential trace divalent cations, as well as highly toxic ones; this competition increases strain on the kidneys exposed to toxic heavy metals (Barbier et al., 2005; Ballatori, 2002). DMT1 has been shown to transport Fe, Zn, Mn, Co, Cd, Cu, Ni, and Pb via a proton-coupled, membrane potential dependant mechanism (Ballatori, 2002). Some toxic metals can also enter a cell by forming complexes that mimic endogenous molecules in their structure. Arsenate and vanadate, for example, act as phosphate mimics both for transport and metabolism, assaulting cellular function by the same mechanism as their initial entry; cromate, selenite and molybdate mimic sulfate in a similar way (Ballatori, 2002). Many of the identified transporters fooled by this mimicry have been localized to the brush border membrane of the renal proximal tubule and epithelial cells. Some divalent metals such as Cd, Ba, and Sr have been shown to enter cells through voltage gated calcium channels. Another important example focused on by Ballatori (2002) is the action of inorganic mercury and methyl mercury (MeHg) that were shown to have high affinity for reduced sulfhydryl groups. These groups are seen on the amino acid cysteine, and importantly on glutathione (GSH), a vital enzymatic antioxidant. MeHg mimics methionine to enter the cell, after which it binds to GSH, and interferes with ATP production (Ballatori, 2002). Uranium has been shown to enter the blood rapidly and then either form stable complexes with plasma proteins, due to its high affinity for phosphate, carboxyl and hydroxyl groups, or binds to bicarbonate in the blood (Keith et al., 2013). In the kidneys, uranium can be released from bicarbonate to combine with other small proteins in the kidney tubular walls, disrupting cellular function (Keith et al., 2013). Uranium has been seen to enter the glomerulus, where it is filtered, via endocytosis as UO+2 binding to anionic sites of proximal tubular epithelial brush borders (Shaki et al., 2012). To further understand the mode of action of heavy metals within the kidneys, many studies have been conducted to determine the specific region primarily damaged. It is also important to note that variation of results may be found in some studies as experimental conditions as well as other factors may influence the mode of action of some metals. Zamora et al. (1998) found that kidney function decrease and cytotoxicity increase were correlated with uranium ingestion. However, no glomerular injury was detected, indicating that chronic uranium ingestion in rats (0.004 µg/kg to 9 µg/kg body weight) damages the proximal tubule and not the glomerulus (Zamora et al., 1998). Homma-Takeda et al. (2013) identifies the kidneys as the major site of depleted uranium toxicity. Studying the kidneys of rats of varying ages, exposed to 0.1-2mg/kg uranyl acetate, they found that the younger kidneys did not flush the uranium out as well. Accumulation of uranium and its damages was seen in the S3 segment of the proximal tubules (Homma-Takeda et al., 2013). Shaki et al. (2012), assessed the mechanism of depleted uranium-induced nephrotoxicity that revealed damage to the mitochondria isolated from uranyl acetate treated rat kidney cells. The damage included oxidative stress, mitochondrial swelling, mitochondrial membrane potential collapse, cytochrome C release, impaired ATP production, and damage to the electron transport chain complexes. Utilizing rat renal brush border vesicles, Goldman et al. (2006) found that exposure to uranyl acetate induced decreased rates of glucose transport, in part due to a decreased number of sodium-coupled glucose transporters; this decreased the ability of the kidneys to reabsorb glucose properly. Berradi et al. (2008) assessed the red blood cell (RBC) count of rats drinking water containing 40mg DU/L and found that chronic exposure to DU causes RBC reduction, pointing to nephrotoxicity as the kidneys play a major role in RBC synthesis. Heavy metals consistently aggregate in the kidneys, and more specifically in the S3 segment of the proximal tubules. Evidence also suggests that uranium and other heavy metals induce nephrotoxicity after endocytosis into cells by disrupting the electron transport chain, inducing oxidative stress. The oxidative stress leads to mitochondrial dysfunction followed by, apoptosis at low doses of uranium and necrosis at  high doses of uranium. Finally, this induces renal injury and tissue damage to the proximal tubules, or nephrotoxicity.

<table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <tbody> <tr> <td>Assay Type & Measured Content</td> <td> Description </td> <td>Dose Range Studied</td> <td> Assay Characteristics (Length/Ease of use/Accuracy) </td> </tr> <tr> <td> Kidney Function Assay Measuring total urinary protein, albumin, transferrin, b2-microglobulin, retinolbinding protein, brush border tubular antigens, N-acetyl-b-Dglucosaminidase activity, serum and urinary creatine (de Burbure et al., 2003) </td> <td>“All analyses of a given parameter were performed under similar experimental conditions in the same laboratories within 6mo of collection. Total urinary protein (Prot-T-U) was determined by the Coomassie blue G250 binding method. Albumin (Alb-U), transferrin (Transf-U), β2-microglobulin (β2m-U), and retinolbinding protein (RBP-U) in urine were quantified by latex immunoassay (Bernard & Lauwerys, 1983). Acceptable limits for precision and accuracy of measurements and external quality controls were the same as those described in the Cadmibel study (Lauwerys et al., 1990). The brush border tubular antigens (BBA-U) were analyzed by a sandwich enzyme-linked immunoassay using monoclonal antibodies (Mutti et al., 1985). The total activity of N-acetyl-β-Dglucosaminidase (NAG-T-U) in urine was determined colorimetrically using a kit (PPR Diagnostics Ltd.) as described elsewhere (Price et al., 1996). Only total NAG (NAG-T) was used for the purpose of this study. Serum and urinary creatinine (Creat-U) were measured by the methods of Heinegard and Tiderström (1973), and Jaffé, respectively (Henry, 1965).” (de Burbure et al., 2003)</td> <td>“The soil contamination in the area varied from 100 to 1700ppm lead (with values higher than 1000ppm in the immediate vicinity of the factories), 0.7 to 233ppm cadmium, and 101 to 22,257ppm zinc, with the highest concentrations being recorded within 500 m of the 2 factories”</td> <td> </td> </tr> <tr> <td> NAG Assay Measuring N-acetyl-b-D-Glucosaminidase urinary content (Lim et al., 2016)</td> <td>“Urinary NAG activity was measured by using NAG Quantitative Kit (Shionogi, Osaka, Japan). After storing a synthetic substrate solution (1 mL) at 37°C for five minutes, the solution was mixed with the supernatant of the urine samples (50 mL) received after centrifugation. After storing it at 37°C for 15 min, stopping solution (2 mL) was added to and mixed with it. By using a spectrophotometer, its fluorescence intensities were measured with a wavelength of 580 nm (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057" style="color:#0563c1; text-decoration:underline">13</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057" style="color:#0563c1; text-decoration:underline">14</a>). Urinary β2-MG was measured by using Enzygnost β2-MG Micro Kit (Behring Institute, Mannheim, Germany). Its method used the principle of solid phase enzyme-linked immunosorbent assay (ELISA). Monoclonal anti-β2-MG antibody and anti-2-MG-horseradish peroxidase conjugate solution were used. After that, color intensities were measured with a wavelength of 450 nm by using a spectrophotometer (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057" style="color:#0563c1; text-decoration:underline">13</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057" style="color:#0563c1; text-decoration:underline">14</a>).” (Lim et al., 2016)</td> <td> Pb: 0.0221ppm (converted from blood Pb µg/dL) Cd: 1.08ppm (converted from Urinary Cd μg/g creatinine)</td> <td>Fast, easy, accurate</td> </tr> <tr> <td> Kidney Dysfunction Assay Measuring BUN and creatinine serum blood levels (Shaki et al., 2012)</td> <td>“For studies in vivo rats were fasted overnight, then animals were divided into two groups, with six rats in each group. The control group (vehicle) received a single intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight). Uranyl acetate was dissolved in normal saline. Rats were treated with single intraperitoneal (i.p.) injections of UA in doses 0.5, 1 and 2 mg/kg body weight. These dosages was selected based on previous studies [28], which is sufficient to induce oxidative stress in kidney without causing death and none died within the duration of experiments. Blood urea nitrogen (BUN) and creatinine, marker of kidney dysfunction, were determined by commercial reagents (obtained from Parsazmoon Co., Iran). The rats were killed by decapitation 24 h after injection. The kidney were immediately removed and placed in ice-cold mitochondria isolation medium (0.225 M D-mannitol, 75 mM sucrose, and 0.2 mM EDTA, pH=7.4)” (Shaki et al., 2012)</td> <td>Control, 0.5, 1, 2 mg/kg Uranyl Acetate (UA) </td> <td>Fast, easy, medium accuracy </td> </tr> </tbody> </table>

Higher order animals (mammals) with functional and complete kidneys

UBERON:0002113

UBERON kidney

Not Specified Not Specified

Al Dera, H. S. (2016). Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats. Saudi Med J, 37(4), 369-378. doi:10.15537/smj.2016.4.13611 Andjelkovic, M., Djordjevic, A. B., Antonijevic, E., Antonijevic, B., Stanic, M., Kotur-Stevuljevic, J., . . . Bulat, Z. (2019). Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney. International Journal of Environmental Research and Public Health, 16, 247. doi:10.3390/ijerph16020274 Arzuaga , X., Rieth, S. H., Bathija, A. & Cooper, G. S. (2010) Renal Effects of Exposure to Natural and Depleted Uranium: A Review of the Epidemiologic and Experimental Data, Journal of Toxicology and Environmental Health, Part B, 13:7-8, 527-545, DOI:10.1080/10937404.2010.509015 Ballatori, N. (2002). Transport of toxic metals by molecular mimicry. Environmental Health Perspectives, 110, 689-694. doi:10.1289/ehp.02110s5689 Barnes, P., Yeboah, J. K., Gbedema, W., Saahene, R. O., & Amoani, B. (2020). Ameliorative effect of vernonia amygdalina plant extract on heavy metal-induced LIver and kidney dysfunction in rats. Advances in Pharmacological and Pharmaceutical Sciences, 2020, 1-7. doi:10.1155/2020/2976905 Barbier, O., Jcquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the  kidney. Nephron Physiology, 99, 105-110. doi:10.1159/000083981 Bonventre, J. V., Vaidya, V. S., Schmouder, R., Feig, P., & Dieterle, F. (2010). Next-generation biomarkers for detecting kidney toxicity. Nature biotechnology, 28(5), 436–440. <a href="https://doi.org/10.1038/nbt0510-436" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1038/nbt0510-436</a> Brzoska, M. M., Kaminski, M., Supernak-Bobko, D., Zwierz, K., & Moniuszko-Jakoniuk, J. (2003). Changes in the strucutre and function of the kidney of rats chronically exposed to cadmium. I. biochemical and histopathological studies. Arch.Toxicol., 77, 344-352. doi:10.1007/s00204-003-0451-1 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 Chtourou, Y., Garoui, E. m., Boudawara, T., & Zeghal, N. (2014). Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. Environ Toxicol, 29, 1147-1154. doi:10.1002/tox.21845 Durante, P., Romero, F., Perez, M., Chavez, M., & Parra, G. (2010). Effect of uric acid on nephrotoxicity induced by mercuric chloride in rats. Toxicology and Industrial Health, 26(3), 163-174. doi:10.1177/0748233710362377 García-Niño, W. R., Tapia, E., Zazueta, C., Zatarain-Barrón, Z. L., Hernández-Pando, R., Vega-García, C. C., & Pedraza-Chaverrí, J. (2013). Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening. Evidence-Based Complementary and Alternative Medicine, (424692), 1-19. doi:10.1155/2013/424692 Goldman, M., Yaari, A., Doshnitzki, Z., Cohen-Luria, R., & Moran, A. (2006). Nephrotoxicity of uranyl acetate: Effect on rat kidney brush border membrane vesicles. Archives of Toxicology, 80(7), 387-393. doi:10.1007/s00204-006-0064-6 Homma-Takeda S, Kokubo T, Terada Y, Suzuki K, Ueno S, Hayao T, Inoue T, Kitahara K, Blyth BJ, Nishimura M, Shimada Y. Uranium dynamics and developmental sensitivity in rat kidney. J Appl Toxicol. 2013 Jul;33(7):685-94. doi: 10.1002/jat.2870. Epub 2013 Apr 26. PMID: 23619997. Keith, S., Faroon, O., N., R., Scinicariello, F., Wilbur, S., Ingerman, L., . . . Diamond, G. (2013). Toxicological profile for uranium. U.S. Department of Health and Human Services. Agency for Toxic Substances and Disease Registry. Kharroubi, W., Dhibi, M., Mekni, M., Haouas, Z., Chreif, I., Neffati, F., . . . Sakly, R. (2014). Sodium arsenate induce changes in fatty acids profiles and oxidative damage in kidney of rats. Environ Sci Pollut Res, 21, 12040-12049. doi:10.1007/s11356-014-3142-y Lunyera, J., & Smith, S. R. (2017). Heavy metal nephropathy: Considerations for exposure analysis. Kidney International, 92, 548-550. doi:http://dx.doi.org/10.1016/j.kint.2017.04.043 Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: Heavy metal nephrotoxicity. Revista Nefrologia, doi:10.3265/Nefrologia.pre2012.Jan.10928 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 Soussi, A., Gargouri, M., & El Feki, A. (2018). Effects of co-exposure to lead and zinc on redox status, kidney variables and histopathology in adult albino rats. Toxicology and Industrial Health, 34(7), 469-480. doi:10.1177/0748233718770293 Spreckelmeyer, S., Estrada-Ortiz, N., Prins, G. G. H., van der Zee, M., Gammelgaard, B., Sturup, S., . . . Casini, A. (2017). On the toxicity and transportation mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent. Metallomics, 9, 1786. doi:10.1039/c7mt00271h Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biological Trace Element Research, 189, 95-108. doi:10.1007/s12011-018-1443-6 Weber, E. J., Himmelfarb, J., & Kelly, E. J. (2017). Concise review: Current emerging biomarkers of nephrotoxicity. Curr Opin Toxicol., 4, 16-21. doi:10.1016/j.cotox.2017.03.002 Yeh, Y., Lee, Y., Hsieh, Y., & Hwang, D. (2011). Dietary taurine reduces zinc-induced toxicity in male wistar rats. Journal of Food Science, 76(4), 90-98. doi:10.1111/j.1750-3841.2011.02110.x Zamora, L. M., Tracy, B. L., Zielinski, J. M., Meyerhof, D. P., & Moss, M. A. (1998). Chronic ingestion of uranium in drinking water: A study of kidney bioeffects in humans. Toxicological Sciences, 43(1), 68-77. doi:10.1006/toxs.1998.242 AOPWiki 2016-11-29T18:41:27

2022-03-04T10:58:19

<upstream-id>8c540c8c-4a01-4812-99d8-a349bd3705a2</upstream-id> <downstream-id>17361219-573a-4a99-97e8-691ffd8f4f2a</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430af7cec0> AOPWiki 2017-10-25T08:46:20

2017-10-25T08:46:20

<upstream-id>17361219-573a-4a99-97e8-691ffd8f4f2a</upstream-id> <downstream-id>b0eea298-39ec-4974-b651-43e331bafc21</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430af9ef98> AOPWiki 2017-10-25T08:47:20

2017-10-25T08:47:20

<upstream-id>b0eea298-39ec-4974-b651-43e331bafc21</upstream-id> <downstream-id>6f702f63-535d-48cd-b875-296833d24eed</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430afb5040> AOPWiki 2017-10-25T08:47:43

2017-10-25T08:47:43

<upstream-id>6f702f63-535d-48cd-b875-296833d24eed</upstream-id> <downstream-id>a4a2d1ad-89b2-4a6b-aabd-d31d66f960d0</downstream-id> Excessive renal tubular cytotoxicity, both apoptotic and necrotic, leads to the eventual failure of the kidneys (Priante et al., 2019). This is because the mass cytotoxicity of renal tubular cells leads to the inability of the nephrons to properly filter nutrients and waste from the blood (Pirante et al., 2019). The kidneys can make compensational adjustments to the nephrons to continue adequate filtration up to the loss of 75% of the nephrons, beyond this amount of nephron loss, the kidneys lose function (Orr and Bridges, 2017).

Renal tubular cells are very important functional units of the nephrons (Priante et al., 2019). The tubular cells are essential for the proper removal of waste material from the blood, as well as retaining essential nutrients, water, and salt levels for homeostatic blood content (Priante et al., 2019). The S3 segment of the proximal tubule in particular is highly susceptible to damage by environmental toxicants (Lentini et al., 2017). Apoptosis is the preferred method of cell death for renal tubule cells, as injured cells need to be removed without inducing an inflammatory response (Priante et al., 2019). By forming apoptotic bodies that can be recycled via phagocytes or epithelial cells, the kidney avoids the induction of an inflammatory response which causes the injury of surrounding, healthy cells. However, when apoptotic bodies are not phagocytosed quickly enough, their membranes can become damaged. This causes the apoptotic bodies to enter secondary necrosis, lysing and releasing their contents to the extracellular space. The immune cells will instigate an inflammatory response as a result, causing the injury to nearby tubular cells through the release of granule contents of by the immune cells (Priante et al., 2019). Remarkably, thanks to compensatory functional, molecular, and structural changes in the kidney, the remaining healthy nephrons are able to function adequately until more than 75% of them die (Orr and Bridges, 2017). After the loss of more than 75% of the nephrons however the remaining nephrons are no longer able to effectively remove environmental toxicants or waste from the filtrate, resulting in failed renal function (Orr and Bridges, 2017).

<h3>Dose Concordance</h3> ... <h3>Temporal concordance</h3> ...   <h3>Incidence concordance</h3> One article showed that rats treated once with 5 mg/kg uranyl acetate showed significantly increased proximal tubular cytotoxicity and significant increase in serum creatinine 3 days after the treatment (Sano et al., 2000).   <h3>Other Evidence</h3> “Chronic exposure: After ingestion or inhalation, cadmium is transported to the liver and to the kidney by metallothionein, which binds cadmium. Signs of cell apoptosis and cytokine pathway activation are common in this syndrome. A typical, chronic tubular-interstitial nephropathy is produced by the accumulation of this metal in the medulla and S1 segment of the proximal tubule.” (Lentini et al., 2017)  “Acute exposure: The ionized free form induces cellular toxicity reducing phosphate and glucose transport and inhibiting mitochondrial respiration, with membrane rupture of the proximal tubular cells of the nephron (<a href="https://www.spandidos-publications.com/10.3892/mmr.2017.6389#b17-mmr-15-05-3413" style="color:blue; text-decoration:underline">17</a>).  “Organic mercury gives skin manifestations and neurological disturbances such as hearing loss, paraesthesia and ataxia. Mercury-related kidney damage can due to tubular dysfunction with elevated urinary excretion of albumin, transferrin, retinol binding protein, and β-galactosidase and a nephrotic syndrome with membranous nephropathy pattern (<a href="https://www.spandidos-publications.com/10.3892/mmr.2017.6389#b21-mmr-15-05-3413" style="color:blue; text-decoration:underline">21</a>).” (Lentini et al., 2017) Orr and Bridges (2017) found that exposure to heavy metals **** “Indeed, it has also been suggested that exposure to heavy metals can negatively alter the function of the remaining functional nephrons [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454951/#B11-ijms-18-01039" style="color:blue; text-decoration:underline">11</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454951/#B12-ijms-18-01039" style="color:blue; text-decoration:underline">12</a>]. These adverse effects could conceivably lead to additional and/or more rapid cell death and glomerulosclerosis, which would further reduce the functional renal mass of the patient.” (Orr & Bridges, 2017) “In the rat, an acute perfusion of Cd2+ caused hypercalciuria, hyperphosphaturia and hypokaliuria without modification of glomerular filtration rate (GFR) [<a href="https://www.karger.com/Article/FullText/83981#ref1" style="color:blue; text-decoration:underline">1</a>]. By contrast, a single, 20-fold lower dose of Pb2+, Hg2+ induced glomerular and tubular damage characterized by a reduced GFR, glycosuria, proteinuria and a rapid obstruction of the tubular system [<a href="https://www.karger.com/Article/FullText/83981#ref13" style="color:blue; text-decoration:underline">13</a>], illustrating that the pattern of nephrotoxicity differs between heavy metals. Therefore, Pb2+ and Hg2+ are more dangerous than Cd2+ because they induce an irreversible renal insufficiency even during acute intoxication.” (Barbier et al., 2005)

There are no currently known inconsistencies or uncertainties for this relationship.

There are several known modulating factors of the relationship between renal tubular cytotoxicity and kidney failure. One modulator of this relationship is age.

There is a defined response-response relationship for renal tubule cytotoxicity leading to kidney failure. The loss of 75% of the nephrons to damage is the threshold for kidney failure (Orr and Bridges, 2017). This is due to the ability of the kidneys to make changes in the structure and function of the remaining nephrons at a molecular level to compensate for the lost nephrons (Orr and Bridges, 2017). The kidneys are able to retain adequate functioning until only 25% of the original nephrons remain, at which point the compensatory changes cannot maintain kidney functioning and kidney failure is final (Orr and Bridges, 2017).

There are no known feedforward/feedback loops that influence this relationship.

The domain of applicability only includes vertebrates, as invertebrates and non-animals do not have kidneys (Mahasen, 2016).

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430afda1d8> AOPWiki 2017-10-25T07:54:27

2022-03-08T11:46:18

Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity

Allie Always

Prof. Dr. Angela Mally Department of Toxicology University of Würzburg Versbacher Str. 9 97078 Würzburg Germany Phone: +49 931 31-81194 Email: mally@toxi.uni-wuerzburg.de (mailto:mally@toxi.uni-wuerzburg.de)

BY-SA

Under Development

1.43

1.0

This Adverse Outcome Pathway describes the sequential key events that link lysosomal overload to kidney toxicity. It is well established that polybasic drugs and compounds with peptidic structure (e.g. aminoglycosides, polymyxins), heavy metals bound to proteins (e.g. Cd-metallothionine) and urinary proteins that pass the glomerular filter may bind to multiligand, endocytic receptors expressed at the brush-boarder of renal tubule cells located within the proximal convoluted tubule (PCT), resulting in proximal tubule cell uptake via receptor-mediated endocytosis (MIE) [1-5]. Due to low lysosomal pH, endocytosed compounds may be trapped within lysosomes and accumulate in this organelle, leading to disruption of lysosomal function (KE1) and lysosomal swelling.  Disturbance of lysosomal function eventually leads to disruption of lysosomes (KE2) and release of reactive oxygen species and cytotoxic lysosomal enzymes, resulting in proximal tubule cell toxicity (KE3) [3, 4, 6]

adjacent

Low

High adjacent

Low

High adjacent

Low

High adjacent

Moderate

High

High Unspecific

Not Specified

All life stages

High Not Specified Not Specified

Although mechanistic data on KEs and KERs in this AOP are mostly derived from studies in rodents, the described AOP presents a general mechanism leading to kidney toxicity in wide range of species, including human, mice, rat, dog, monkey.  The described AOP is not limited to a specific life stage or sex. Human, Mice, Rat, Dog, Monkey

Concordance of dose-response relationships This is still a qualitiative description of the pathway. There is at present no quantitative information on dose-response relationships. Experiments are underway to provide quantitative understanding of dose-response relationships and response-response relationships between upstream and downstream KEs.   Temporal concordance among the key events and adverse outcome The individual KEs are shown to occur prior to or concomitant with the onset of nephrotoxicity.   Strength, consistency, and specificity of association of adverse outcome and initiating event The scientific evidence on the association between inhibition of lysosomal overload initiated by receptor-mediated endocytosis and kidney toxicity (AO) is strong and consistent.   Biological plausibility, coherence, and consistency of the experimental evidence The described AOP is biologically plausible, coherent and supported by experimental data.   Alternative mechanism(s) that logically present themselves and the extent to which they may distract from the postulated AOP There are no alternative mechanism(s) that logically present themselves.   Uncertainties, inconsistencies and data gaps This AOP is plausible and consistent with general biological knowledge. Quantitative information on dose response-relationships as well as response-response relationships for upstream and downstream KEs is needed to support its applicability for the development of alternative in vitro tests for nephrotoxicity testing.

Quantitative data on KERs between upstream and downstream KE are still lacking.

The described AOP is intended to provide a mechanistic framework for the development of in vitro bioactivity assays capable of predicting quantitative points of departure for safety assessment with regard to nephrotoxicity. Such assays may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies (e.g.  OECD Guideline 407; OECD Guideline 407).

High

Moderate

High

1.           Verroust, P.J., et al., The tandem endocytic receptors megalin and cubilin are important proteins in renal pathology. Kidney Int, 2002. 62(3): p. 745-56. 2.           Moestrup, S.K., et al., Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest, 1995. 96(3): p. 1404-13. 3.           Schnellmann, R.G., Toxic Responses of the Kidney, in Casarett and Doull´s Toxicology. The Basic Science of Poisons, C.D. Klaassen, Editor. 2013, Mcgraw-Hill Education Ltd: Kansas City. 4.           Khan, K.N.M. and C.L. Alden, Kidney, in Handbook of Toxicologic Pathology, W.M. Haschek, C.G. Rousseaux, and M.A. Wallig, Editors. 2002, Academic Press: San Diego. 5.           Thevenod, F., Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol, 2003. 93(4): p. p87-93. 6.           Liu, W.J., et al., Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells. Am J Physiol Renal Physiol, 2015. 308(6): p. F639-49. AOPWiki 2017-10-25T08:13:54

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