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Relationship: 3115

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, essential element imbalance leads to Increase, ROS

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, essential element imbalance

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, ROS

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Essential element imbalance leads to reproductive failure via oxidative stress	adjacent			Travis Karschnik (send email)	Under development: Not open for comment. Do not cite

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Murinae gen. sp.	Murinae gen. sp.	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult, reproductively mature	High
Adult	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Essential elements including copper, zinc, and iron are required for normal cellular processes and therefore are subject to mechanisms which regulate their function. In contrast, nonessential elements e.g., mercury, cadmium, and lead don’t have known nutritive value and accordingly, no dedicated mechanisms have evolved for their uptake in most animal species (Bridges and Zalups 2005). In spite of this, these toxic metals still enter various cells (Clarkson 1993, Ballatori 2002, Zalups 2000, Zalups and Ahmad 2003).

The concept of mimicry, in both molecular and ionic forms, has been hypothesized as mechanisms by which these metal species can enter target cells. Molecular mimicry refers to the bonding of metal ions to nucleophilic groups on certain biomolecules results in the formation of organo-metal complexes that can behave or serve as a structural and/or functional homolog of other endogenous biomolecules or the molecule to which the metal ion has bonded (Clarkson 1993, Ballatori 2002, Zalups 2000). Alternatively, ionic mimicry refers to the ability of an unbound, native, cationic species of a metal to mimic an essential element or cationic form of that element (Clarkson 1993, Wetterhahn-Jennette 1981, Zalups and Ahmad 2003). Either type of mimic may also be classified as structural or functional mimics. A structural mimic refers to an elemental or molecular species that is similar in size and shape to another element or molecule. A functional mimic is one that can elicit the same effect, i.e., physiological response, as the native element or molecule (Bridges and Zalups 2005).

Essential element imbalance, resulting from molecular and ionic mimicry, causing either deficiency or overload, can inhibit the antioxidant ability of the elements that are mimicked i.e., Selenium, Zinc, Copper, Magnesium, and Manganese, among others.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This KER was identified as part of an Environmental Protection Agency effort to increase the impact of AOPs published in the peer-reviewed literature, but heretofore unrepresented in the AOP-Wiki, by facilitating their entry and update. The originating work for this AOP was da Silva, J., Goncalves, R. V., de Melo, F. C. S. A., Sarandy, M. M., & da Matta, S. L. P. (2021). Cadmium exposure and testis susceptibility: A systematic review in murine models. Biological Trace Element Research, 199(7), 2663-2676. This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.

Evidence for the originating publication was assembled using Medline/PubMed and Scopus in September 2018. For all databases, the search filters were based on three complementary levels: (i) animals, (ii) testis, and (iii) cadmium and studies that didn't evaluate the Cd exposure in the testicular histomorphology of murine models were excluded.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The primary antioxidant defense systems are enzymatic reaction systems in the body, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), etc. (Erdogan et al., 2005, Valdivia et al., 2007). Low molecular weight, non-enzymatic antioxidants also play an important role in the antioxidant protective system by assisting enzyme activity. These include glutathione, pantothenic acid, vitamins and minerals, such as zinc, selenium, and copper (Agarwal et al., 2004, Wolksi 2011). Cadmium exposure has been related to an increase of ROS and to induction of oxidative stress through indirect mechanisms: the first consists in Cd binding to sulfhydryl groups of ROS scavengers, which determines an alteration of their regulatory activity (Stohs and Bagchi 1995, Valko et al., 2005), and the second is driven by interference between Cd and selenium, with major affected targets being the glutathione (GSH) system and, particularly, the GSH peroxidase (GSH-Px) (Ren et al., 2012, Sugawara et al., 1986, Omaye and Tappel 1975, Sugawara and Sugawara 1984, Li et al., 2010, Abarikwu et al., 2013, Yiin et al., 1999). Both processes result in the production of ROS, such as superoxide ion, hydrogen peroxide and hydroxyl radicals (Stohs and Bagchi 1995, Valko et al., 2005). Selenium is a structural component of selenoproteins, comprising antioxidant enzymes, such as GSH-Px (Dodig and Cepelak, Flohe et al., 1973) and which catalyzes the reduction of hydrogen peroxide and organic peroxides, including phospholipids peroxides. Cadmium can also replace calcium in calcium-binding proteins, causing disruption or cessation of activity, which can lead to oxidative stress (El-Demerdash et al., 2004).

Cd interaction with ROS scavengers is mainly mediated by the displacement of Zn and Cu from antioxidant enzymes. This is a molecular mimicry which also precipitates conformational changes and impairment in the activity of the enzymes. Additionally, the increased Cu concentration in the cell also induces ROS production (Pillai and Gupta 2005, Yang et al., 2000, Hanna and Mason 1992). Another mechanism of Cd-induced oxidative stress is related to Cd interference with Se, and consequent interference with reduced GSH, oxidized GSH, GSH-Px, GSH reductase and catalase activities. Another route Cd may induce oxidative damage is by enhancing peroxidation of membrane lipids and altering the antioxidant system of the cells (Sarkar et al. 1995)

Cd and Zinc share similar chemical properties and bind to biological macromolecules containing sulphydryl, hydroxyl and nitroxyl groups. Although Cd ion is larger than Zn ion, Cd has a higher affinity for sulphydryl-containing proteins and nucleic acids, and substitutes for Zn through molecular mimicry, in the presence of excess Cd (Jacobson and Turner 1980). Based on their similarities Cd can potentially interfere with several Zn-mediated biological processes. Zinc is an antioxidant essential trace mineral that acts by neutralizing free radical generation (Powell 2000). Zn protection against the cytotoxicity of Cd may be related to the maintenance of normal redox balance inside the cell (Souza et al. 2004). Bray and Bettger 1990 suggested Zn could exert a direct antioxidant action by occupying the iron or copper binding sites of lipids, proteins, and DNA. Further, zinc-deficient male rats, as a result of Cd exposure, had higher levels of LPO, protein oxidation, and decreased SOD activity, which lead to reduced testicular growth and oxidative stress (Oteiza et al., 1999).

Thévenod 2009 indicated that the effect of Cd on the cellular antioxidant enzymatic system is mediated by inhibition of the mitochondrial electron transport chain. Furthermore, displacement of redox active metals has also been proposed to explain oxidative stress and the antioxidant reaction in response to Cd toxicity (Cupertino et al., 2017).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

PUBLICATION	SPECIES	DESCRIPTION
Amara et al., 2008	Rat	Rats exposed to Cd displayed significant increases in MDA and metallothionein concentrations in the testes. Cadmium exposure significantly decreased the GPx, mitochondrial Mn-SOD, cytosolic CuZn-SOD, and CAT activities in the testes.
Amara et al. 2006	Rat	Cd induced a reduction in liver and kidney GPx, CuZn-SOD, Mn-SOD and CAT activities. Moreover, Cd exposure increased hepatic and renal MDA concentration. The same treatment increased the 8-oxodGuo level in liver and kidney. Our investigations reported that cadmium toxicity implicated probably reactive oxygen spices leading to oxidative stress in rat tissues confirmed by the decrease of antioxidant enzymes activity and the LPO.
He et al., 2008	Mouse	To analyze the role of Nrf2 in the toxic response to Cd, mouse embryonic fibroblast cells (MEF) derived from Nrf2 wild-type (Nrf2+/+) and knockout (Nrf2-/-) mice were treated with Cd, and the production of superoxide anion radical was measured. Cd induced oxidative stress in both wild-type and Nrf2-null cells dose dependently.
Liu et al., 2008	Rat	Cd treatment doubled the basal ESR signal for POBN adducts. Acute Cd exposure induces in vivo hepatic free radical generation as evidenced by POBN-trapped radical metabolites formed in the liver and excreted into the bile.
Yiin et al., 1999	Rat	There was a significant increase in lipid peroxidation products in testes following treatment with all doses of metal used beside the 25 μg/kg Cd.
Oteiza et al., 1999	Rat	Rats (31-day-old) were injected s.c. with a single dose of either saline or CdCl2. By 48 h post-injection there was a marked increase in TBARS concentration, and a marked decrease in glutamine synthetase activity. Testes TBARS concentrations were significantly higher in the zinc-deficient rats than in controls.
Arabi and Mohammadpour 2006	Cow	The results from this analysis show that Cd at the various concentrations (50–750 μmol/L) elevated the MDA level/LPO rate in bull sperm suspensions in a concentration-dependent manner. There was a positive correlation between the concentration of Cd and the LPO rate.
Hart et al., 1999	Rat	After 8 h of Cd treatment, steady-state levels of MT-1 mRNA, GST-α mRNA, and γ-GCS mRNA increased approximately 23-, 5-, and 3-fold, respectively, compared to their mRNA levels in cells that were not exposed to Cd. However, the expression of γ-GCS expression returned to control levels after 24 h of treatment whereas MT-1 and GST-α expression did not. The GST-α mRNA level in Cd-exposed cells was elevated to approximately the same extent above control at both time points. In contrast, the magnitude of MT-1 induction in Cd-exposed cells was 90% lower at 24 h than at 8 h.
Manca et al., 1994	Rat	Cadmium induced a dose-related increase in lung LPO as measured by total lung TBARS.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Liu et al., 2009 showed that, contrary to direct ESR evidence for ROS generation following acute Cd overload, ESR evidence for free radical generation following long-term, low-dose Cd exposure is often obscure. They showed that mice given a diet containing 100 ppm CdCl2 for 6 months, followed by injection of POBN did not enhance the POBN-trapped radicals in the liver and kidneys, nor did it increase the hepatic and renal lipid peroxidation levels.

Other examples of a lack of ROS production following chronic Cd exposures are characterized as follows.

A prolonged Cd exposure (100 ppm, 23 weeks) through the drinking water didn’t produce overt changes in cellular redox status and lipid peroxidation levels (Thijssen et al., 2007).
Dietary Cd exposure (up to 80 ppm) for one year even decreases lipid peroxidation levels in the liver and kidney of the bank vole (Wlostowski et al., 2000).
A single oral dose of Cd (20 mg/kg) initially increased hepatic lipid peroxidation levels and iron concentrations 5 hr after Cd administration in mice, but repeated oral doses (10 mg/kg, daily for 14 days) produced no change or a slightly decrease in hepatic lipid peroxidation levels (Djukic-Dosic et al., 2008).
ROS tolerance is also seen with a long-term (one year) injection of Cd at low levels (0.3 mg/kg, 3 days/week), without increases in tissue lipid peroxidation levels (Kamiyama et al., 1995).
In rats given chronic Cd injections (0.6 mg/kg for 12 weeks), kidney injury is evident with dramatic increase in expression of kidney injury molecule-1 and MT (Prozialeck et al., 2007), but the changes in the expressions of ROS-related genes and oxidative DNA damage genes are not appreciable.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

PUBLICATION	TESTED CONCENTRATIONS	EFFECT CONCENTRATION
Amara et al., 2008	In vivo - Drinking water - 40 mg/L	40 mg/L
Amara et al. 2006	In vivo - Drinking water - 40 mg/L	40 mg/L
He et al., 2008	In vitro - 2, 5, 10, 50, 100 μM	Induction of ROS required 50 μM Cd in the wild type. Markedly elevated ROS production was observed in Nrf2-null cells treated with as low as 2 μM d, indicating that loss of Nrf2 function increased oxidative stress in cells both under basal conditions and in the presence of Cd.
Liu et al., 2008	In vivo - IP injection - 40 μM/kg	40 μM/kg
Yiin et al., 1999	In vivo - IP injection - 25, 125, 500, and 1250 ug/kg	There was a significant increase in lipid peroxidation products in testes following treatment with all doses of metal used beside the 25 μg/kg Cd.
Oteiza et al., 1999	In vivo - SC injection - 2 mg/kg body weight	2 mg/kg body weight
Arabi and Mohammadpour 2006	In vitro - 50, 250, 500, and 750 μM/L	Significant increase in MDA level at 250 μM/L
Hart et al., 1999	In vitro - 20 μM	20 μM
Manca et al., 1994	In vivo - IP injection - 50, 250, and 1000 ug/kg bodyweight	Cadmium induced a dose-related increase in lung LPO as measured by total lung TBARS but significant differences were only seen following the administration of 250 and 1000 ug/kg bodyweight.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

See UNCERTAINTIES AND INCONSISTENCIES section for information about some chronic exposure outcomes.

PUBLICATION	STUDY DURATION	EFFECT DURATION
Amara et al., 2008	30 days	Measurements at a single time, 30 days.
Amara et al. 2006	4 weeks	Measurements at a single time, 4 weeks
He et al., 2008	6 hours	Measurements at a single time, 6 hours
Liu et al., 2008	40-60 minutes	Measurements at a single time, 40-60 minutes (See UNCERTAINTIES AND INCONSISTENCIES section for information about some chronic exposure outcomes)
Yiin et al., 1999	6-72 hours	A significant rise was noted at 72 h with the 25 μg dose. The 500 μg/kg Cd dose markedly altered testes lipid peroxidation at 24 and 72 h
Oteiza et al., 1999	6-48 hours	48 hours was the shortest time period eliciting marked increase in TBARS and decrease in glutaimen synthetase activity. Zinc deficient rats showed significant differences in TBARS and glutamine synthetase activity after 24 hours.
Arabi and Mohammadpour 2006	60 minutes	Measurements at a single time, 60 minutes after injection
Hart et al., 1999	2-24 hours	After 8 h of Cd treatment, steady-state levels of MT-1 mRNA, GST-α mRNA, and γ-GCS mRNA increased approximately 23-, 5-, and 3-fold, respectively, compared to their mRNA levels in cells that were not exposed to Cd. However, the expression of γ-GCS expression returned to control levels after 24 h of treatment whereas MT-1 and GST-α expression did not.
Manca et al., 1994	24 hours	Measurements at a single time, 24 hours

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

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

Abarikwu, S. O., Iserhienrhien, B. O., & Badejo, T. A. (2013). Rutin-and selenium-attenuated cadmium-induced testicular pathophysiology in rats. Human & experimental toxicology, 32(4), 395-406.

Agarwal, A., Nallella, K. P., Allamaneni, S. S., & Said, T. M. (2004). Role of antioxidants in treatment of male infertility: an overview of the literature. Reproductive biomedicine online, 8(6), 616-627.

Amara, S., Abdelmelek, H., Garrel, C., Guiraud, P., Douki, T., Ravanat, J. L., ... & Rhouma, K. B. (2006). Influence of static magnetic field on cadmium toxicity: study of oxidative stress and DNA damage in rat tissues. Journal of Trace Elements in Medicine and Biology, 20(4), 263-269.

Amara, S., Abdelmelek, H., Garrel, C., Guiraud, P., Douki, T., Ravanat, J. L., ... & Rhouma, K. B. (2008). Preventive effect of zinc against cadmium-induced oxidative stress in the rat testis. Journal of Reproduction and Development, 54(2), 129-134.

Arabi, M., & Mohammadpour, A. A. (2006). Adverse effects of cadmium on bull spermatozoa. Veterinary research communications, 30, 943-951.

Ballatori, N. (2002). Transport of toxic metals by molecular mimicry. Environmental health perspectives, 110(suppl 5), 689-694.

Bray, T. M., & Bettger, W. J. (1990). The physiological role of zinc as an antioxidant. Free Radical Biology and Medicine, 8(3), 281-291.

Bridges, C. C., and Zalups, R. K. (2005). Molecular and ionic mimicry and the transport of toxic metals. Toxicology and applied pharmacology, 204(3), 274-308

Burukoğlu, D., & Bayçu, C. (2008). Protective effects of zinc on testes of cadmium-treated rats. Bulletin of environmental contamination and toxicology, 81, 521-524.

Clarkson, T. W. (1993). Molecular and ionic mimicry of toxic metals. Annual review of pharmacology and toxicology, 33(1), 545-571.

Djukić-Ćosić, D., Jovanović, M. Ć., Bulat, Z. P., Ninković, M., Maličević, Ž., & Matović, V. (2008). Relation between lipid peroxidation and iron concentration in mouse liver after acute and subacute cadmium intoxication. Journal of Trace Elements in Medicine and Biology, 22(1), 66-72.

do Carmo Cupertino, M., Novaes, R. D., Santos, E. C., Bastos, D. S. S., Dos Santos, D. C. M., Fialho, M. D. C. Q., & da Matta, S. L. P. (2017). Cadmium-induced testicular damage is associated with mineral imbalance, increased antioxidant enzymes activity and protein oxidation in rats. Life sciences, 175, 23-30.

Dodig, S., & ČEPELAK, I. (2004). The facts and controverses about selenium. Acta pharmaceutica, 54(4), 261-276.

Erdogan, Z., Erdogan, S., Celik, S., & Unlu, A. (2005). Effects of ascorbic acid on cadmium-induced oxidative stress and performance of broilers. Biological trace element research, 104, 19-31.

El-Demerdash, F.M., Yousef, M.I., Kedwany, F.S. and Baghdadi, H.H., 2004. Cadmium-induced changes in lipid peroxidation, blood hematology, biochemical parameters and semen quality of male rats: protective role of vitamin E and β-carotene. Food and Chemical Toxicology, 42, 1563–1571

Flohe, L., Gunzler, W. A., & Schock, H. H. (1973). Glutathione peroxidase: a selenoenzyme. FEBS lett, 32(1), 132-134. Flohe et al., 1973

Foresta, C., Flohé, L., Garolla, A., Roveri, A., Ursini, F., & Maiorino, M. (2002). Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Biology of reproduction, 67(3), 967-971.

Hanna, P. M., & Mason, R. P. (1992). Direct evidence for inhibition of free radical formation from Cu (I) and hydrogen peroxide by glutathione and other potential ligands using the EPR spin-trapping technique. Archives of Biochemistry and Biophysics, 295(1), 205-213.

Hart, B. A., Lee, C. H., Shukla, G. S., Shukla, A., Osier, M., Eneman, J. D., & Chiu, J. F. (1999). Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. Toxicology, 133(1), 43-58.

Hawkes, W. C., and Turek, P. J. (2001). Effects of dietary selenium on sperm motility in healthy men. Journal of andrology, 22(5), 764-772.

He, X., Chen, M. G., & Ma, Q. (2008). Activation of Nrf2 in defense against cadmium-induced oxidative stress. Chemical research in toxicology, 21(7), 1375-1383.

Jacobson, K. B., & Turner, J. E. (1980). The interaction of cadmium and certain other metal ions with proteins and nucleic acids. Toxicology, 16(1), 1-37.

Kamiyama, T., Miyakawa, H., Li, J. P., Akiba, T., Liu, J. H., Liu, J. H., ... & Sato, C. (1995). Effects of one-year cadmium exposure on livers and kidneys and their relation to glutathione levels. Research communications in molecular pathology and pharmacology, 88(2), 177-186.

Kaushal, N., & Bansal, M. P. (2009). Diminished reproductive potential of male mice in response to selenium‐induced oxidative stress: Involvement of HSP70, HSP70‐2, and MSJ‐1. Journal of biochemical and molecular toxicology, 23(2), 125-136.

Kjellstrom, T., and Nordberg, G. F. (1978). A kinetic model of cadmium metabolism in the human being. Environmental research, 16(1-3), 248-269.

Li, J. L., Gao, R., Li, S., Wang, J. T., Tang, Z. X., & Xu, S. W. (2010). Testicular toxicity induced by dietary cadmium in cocks and ameliorative effect by selenium. Biometals, 23, 695-705.

Liu, J., Qu, W., & Kadiiska, M. B. (2009). Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicology and applied pharmacology, 238(3), 209-214.

Liu, J., Qian, S. Y., Guo, Q., Jiang, J., Waalkes, M. P., Mason, R. P., & Kadiiska, M. B. (2008). Cadmium generates reactive oxygen-and carbon-centered radical species in rats: insights from in vivo spin-trapping studies. Free Radical Biology and Medicine, 45(4), 475-481.

Ma, D., Hou, Y., Du, L., Li, N., Xuan, R., Wang, F., ... & Wang, L. (2013). Oxidative damages and ultrastructural changes in the sperm of freshwater crab Sinopotamon henanense exposed to cadmium. Ecotoxicology and environmental safety, 98, 244-249.

Manca, D., Ricard, A. C., Van Tra, H., & Chevalier, G. (1994). Relation between lipid peroxidation and inflammation in the pulmonary toxicity of cadmium. Archives of toxicology, 68, 364-369.

Maitani, T., & Suzuki, K. T. (1986). Essential metal contents and metallothionein-like protein in testes of mice after cadmium administration. Toxicology, 40(1), 1-12.

Messaoudi, I., Banni, M., Saïd, L., Saïd, K., & Kerkeni, A. (2010). Involvement of selenoprotein P and GPx4 gene expression in cadmium-induced testicular pathophysiology in rat. Chemico-biological interactions, 188(1), 94-101.

Migliarini, B., Campisi, A. M., Maradonna, F., Truzzi, C., Annibaldi, A., Scarponi, G., & Carnevali, O. (2005). Effects of cadmium exposure on testis apoptosis in the marine teleost Gobius niger. General and Comparative Endocrinology, 142(1-2), 241-247.

Omaye, S. T., & Tappel, A. L. (1975). Effect of cadmium chloride on the rat testicular soluble selenoenzyme, glutathione peroxidase. Research Communications in Chemical Pathology and Pharmacology, 12(4), 695-711.

Oteiza, P. I., Adonaylo, V. N., & Keen, C. L. (1999). Cadmium-induced testes oxidative damage in rats can be influenced by dietary zinc intake. Toxicology, 137(1), 13-22.

Pillai, A., & Gupta, S. (2005). Antioxidant enzyme activity and lipid peroxidation in liver of female rats co-exposed to lead and cadmium: effects of vitamin E and Mn2+. Free radical research, 39(7), 707-712.

Powell, S. R. (2000). The antioxidant properties of zinc. The Journal of nutrition, 130(5), 1447S-1454S.

Prozialeck, W. C., Vaidya, V. S., Liu, J., Waalkes, M. P., Edwards, J. R., Lamar, P. C., ... & Bonventre, J. V. (2007). Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. Kidney international, 72(8), 985-993.

Ren, X. M., Wang, G. G., Xu, D. Q., Luo, K., Liu, Y. X., Zhong, Y. H., & Cai, Y. Q. (2012). The protection of selenium on cadmium-induced inhibition of spermatogenesis via activating testosterone synthesis in mice. Food and chemical toxicology, 50(10), 3521-3529.

Roychoudhury, S., Massanyi, P., Bulla, J., Choudhury, M. D., Lukac, N., Filipejova, T., ... & Almasiova, V. (2010). Cadmium toxicity at low concentration on rabbit spermatozoa motility, morphology and membrane integrity in vitro. Journal of Environmental Science and Health Part A, 45(11), 1374-1383.

Selvaraju, S., Nandi, S., Gupta, P. S. P., & Ravindra, J. P. (2011). Effects of heavy metals and pesticides on buffalo (Bubalus bubalis) spermatozoa functions in vitro. Reproduction in domestic animals, 46(5), 807-813.

Shalini, S., & Bansal, M. P. (2008). Dietary selenium deficiency as well as excess supplementation induces multiple defects in mouse epididymal spermatozoa: understanding the role of selenium in male fertility. International journal of andrology, 31(4), 438-449.

Singhal, R. L., & Merali, Z. (1979). Biochemical toxicity of cadmium. Cadmium toxicity, 61-112.

Souza, V., Escobar, M. D. C., Bucio, L., Hernandez, E., & Gutierrez-Ruiz, M. C. (2004). Zinc pretreatment prevents hepatic stellate cells from cadmium-produced oxidative damage. Cell biology and toxicology, 20, 241-251.

Stohs, S. J., & Bagchi, D. (1995). Oxidative mechanisms in the toxicity of metal ions. Free radical biology and medicine, 18(2), 321-336.

Sugawara, N., & Sugawara, C. (1984). Selenium protection against testicular lipid peroxidation from cadmium. Journal of Applied Biochemistry, 6(4), 199-204.

Sugawara, N., Koike, K., Taguchi, K., Tsukakubo, T., Nihei, T., Yoshida, Y., ... & Miyake, H. (1986). Time dependent effects of selenium on cadmium-induced acute mouse testicular damage. The Journal of Toxicological Sciences, 11(4), 303-312.

Sugawara, N., Hirohata, Y., & Sugawara, C. (1989). Testicular dysfunction induced by cadmium and its improvement caused by selenium in the mouse. Journal of Environmental Pathology, Toxicology and Oncology: Official Organ of the International Society for Environmental Toxicology and Cancer, 9(1), 53-64.

Thévenod, F. (2009). Cadmium and cellular signaling cascades: to be or not to be?. Toxicology and applied pharmacology, 238(3), 221-239.

Thijssen, S., Cuypers, A., Maringwa, J., Smeets, K., Horemans, N., Lambrichts, I., & Van Kerkhove, E. (2007). Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys. Toxicology, 236(1-2), 29-41.

Valdivia, P. A., Zenteno-Savín, T., Gardner, S. C., & Aguirre, A. A. (2007). Basic oxidative stress metabolites in eastern Pacific green turtles (Chelonia mydas agassizii). Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 146(1-2), 111-117.

Valko, M. M. H. C. M., Morris, H., & Cronin, M. T. D. (2005). Metals, toxicity and oxidative stress. Current medicinal chemistry, 12(10), 1161-1208.

Valko, M., Rhodes, C. J. B., Moncol, J., Izakovic, M. M., & Mazur, M. (2006). Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-biological interactions, 160(1), 1-40.

Wang, L., Xu, T., Lei, W. W., Liu, D. M., Li, Y. J., Xuan, R. J., & Ma, J. J. (2011). Cadmium-induced oxidative stress and apoptotic changes in the testis of freshwater crab, Sinopotamon henanense. PLoS One, 6(11), e27853.

Wetterhahn-Jennette, K. (1981). The role of metals in carcinogenesis: biochemistry and metabolism. Environ Health Perspect, 40(233), 52.

Wlostowski, T., Krasowska, A., & Godlewska-Zylkiewicz, B. (2000). Dietary cadmium decreases lipid peroxidation in the liver and kidneys of the bank vole (Clethrionomys glareolus). Journal of trace elements in medicine and biology, 14(2), 76-80.

Wolksi JK (2011). Role of trace elements and vitamins in male infertility] Przegl Urol.;(Suppl 4):1–4.

Yang, M. S., Lai, K. P., Cheng, K. Y., & Wong, C. K. C. (2000). Changes in endogenous Zn and Cu distribution in different cytosolic protein fractions in mouse liver after administration of a single sublethal dose of CdCl2. Toxicology, 154(1-3), 103-111.

Yiin, S. J., Chern, C. L., Sheu, J. Y., & Lin, T. H. (1999). Cadmium induced lipid peroxidation in rat testes and protection by selenium. Biometals, 12, 353-359.

Zalups, R. K. (2000). Molecular interactions with mercury in the kidney. Pharmacological reviews, 52(1), 113-144.

Zalups, R. K., and Ahmad, S. (2003). Molecular handling of cadmium in transporting epithelia. Toxicology and applied pharmacology, 186(3), 163-188.