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Event: 709

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Cytotoxicity (renal tubular cell)

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase, Cytotoxicity (renal tubular cell)
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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
kidney tubule cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
cell death kidney tubule cell increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
α2u-globulin- renal adenomas/carcinomas KeyEvent Charles Wood (send email) Under Development: Contributions and Comments Welcome
Inhibition of mitochondrial DNA polymerase gamma leading to kidney toxicity KeyEvent Angela Mally (send email) Under development: Not open for comment. Do not cite Under Development
Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity KeyEvent Angela Mally (send email) Under development: Not open for comment. Do not cite Under Development
Renal protein alkylation leading to kidney toxicity KeyEvent Angela Mally (send email) Not under active development Under Development
Inhibition of Mt-ETC complexes leading to kidney toxicity KeyEvent Baki Sadi (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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).

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).
 

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).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
Assay Type & Measured Content Description Dose Range Studied

Assay Characteristics

(Length/Ease of use/Accuracy)

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)
“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) “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”  

N-ACETYL-b-D-GLUCOSAMINIDASE (NAG) ASSAY

Measuring NAG urinary content

(Lim et al., 2016)
“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 (13,14). 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 (13,14).” (Lim et al., 2016) Cd & Pb Fast, easy, accurate

MTT Assay (cytotoxicity)

Measuring Cell Viability

(Thiebault et al., 2007; Shaki et al., 2012)
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.

50, 100 and 500 μM of uranyl acetate;

0-1000µM U

Long

Easy/Difficult

High accuracy (mathematical measurement)

Medium Precision

LDH Cytotoxicity Assay

Measuring Necrosis via Lactate Dehydrogenase release

(Thiebault et al., 2007)
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.  15, 30 µM Cd Fast, easy, high accuracy

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)
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. 0-800µM U Long, difficult, high accuracy

“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)

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

All animals with kidneys containing renal proximal tubules.

References

List of the literature that was cited for this KE description. More help

 

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2014). Molecular biology of the cell. New York: Garland Science. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK21054/

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). Size-dependent toxicity of metal oxide particles—A comparison between nano- and micrometer size. Toxicology Letters, 188(2), 112-118. doi:10.1016/j.toxlet.2009.03.014

Lim, H., Lim, J. A., Choi, J. H., Kwon, H. J., Ha, M., Kim, H., & Park, J. D. (2016). Associations of Low Environmental Exposure to Multiple Metals with Renal Tubular Impairment in Korean Adults. Toxicological research, 32(1), 57–64. doi:10.5487/TR.2016.32.1.057

Liu, S., Xu, L., Zhang, T., Ren, G., & Yang, Z. (2010). Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells. Toxicology, 267, 172-177. doi:10.1016/j.tox.2009.11.012

Liu, X., Yang, W., Guan, Z., Yu, W., Fan, B., Xu, N., & Liao, D. J. (2018). There are only four basic modes of cell death, although there are many ad-hoc variants adapted to different situations. Cell & Bioscience, 8(1), 6. doi:10.1186/s13578-018-0206-6

Miller, A. C., Stewart, M., Brooks, K., Shi, L., & Page, N. (2002). 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). Extract from aronia melanocarpa L. berries protects against cadmium-induced lipid peroxidation and oxidative damage to proteins and DNA in the liver: A study using a rat model of environmental human exposure to this xenobiotic. Nutrients, 11, 758. doi:10.3390/nu11040758

Nair, P., Lu, M., Petersen, S., & Ashkenazi, A. (2014). Chapter five - apoptosis initiation through the cell-extrinsic pathway. Methods in Enzymology, 544, 99-128. doi:https://doi.org/10.1016/B978-0-12-417158-9.00005-4

Ozoren, N., & El-Deiry, W. S. (2002). WS. Defining characteristics of types I and II apoptotic cells in response to TRAIL.4(6), 551-557. doi:10.1038/sj.neo.7900270

Pan, Y., Leifer, A., Ruau, D., Neuss, S., Bonrnemann, J., Schmid, G., . . . Jahnen-Dechent, W. (2009). Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(8), 2067-2076. doi:10.1002/smll.200900466

Priante, G., Gianesello, L., Ceol, M., Del Prete, D., & Anglani, F. (2019). Cell death in the kidney. International Journal of Molecular Sciences, 20(14), 3598. doi: 10.3390/ijms20143598. doi:10.3390/ijms20143598 [doi]

Rouas, C., Bensoussan, H., Suhard, D., Tessier, C., Grandcolas, L., Rebiere, F., . . . Gueguen, Y. (2010). Distribution of soluble uranium in the nuclear cell compartment at subtoxic concentrations. Chemical Research in Toxicology, 23(12), 1883-1889. doi:10.1021/tx100168c

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

Small, D. M., Sanchez, W. Y., Roy, S. F., Morais, C., Brooks, H. L., Coombes, J. S., . . . Gobe, G. (2018). N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenousantioxidant responses. American Physiological Society - Renal Physiology, 314, F956-F968. doi:10.1152/ajprenal.00057.2017

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

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, https://doi.org/10.1093/toxsci/kfj106Elmore, 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