Albert Science International Organization

ARTICLE DESCRIPTION: 

Amit Gupta, Metal induced testicular toxicity, ASIO Journal of Experimental Pharmacology & Clinical Research (ASIO-JEPCR), 2020, 6(1): 41-53.

ARTICLE TYPE: REVIEW

Affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, U.P., India.

Doi: 10.2016-37245516/;

DOI Link :: http://doi-ds.org/doilink/07.2020-84816251/

ABSTRACT:

Metal exposure leads to severe damage in male reproductive organs affecting male fertility. Although many of the metals are essential for various biological processes but on the other hand, these essential metals become toxic with the increasing dose and exposure. The primary objective of this review article is to find out the various metal induced toxicity on the reproductive system of male, especially on testicular system. The main aim is to collect the all data in a cumulative way and to compile all of these and represent them in a tabulated form. The overall result of this review offer a confirmation that certain transition metals such as As, Cd, Cr, Hg, Mn, Mo, Pb, Ni, V and Zn may adversely affect male reproductive functions such as spermatogenesis, sperm quality, secretory functions of accessory glands, libido, fertility, serum testosterone level and antioxidant defense system. Most of the reports on the reproductive toxicity of transition metals are from experimental animal studies.

Keywords: Metal toxicity, reproductive system, testicular toxicity, spermatogenesis.

1. Carbone P, Giordano F, Nori F, Mantovani A and Taruscio D: The possible role of endocrine disrupting chemicals in the aetiology of cryptorchidism and hypospadias: A population-based case control study in ruralsicily. Int. J. Androl. 2007; 30:3-13.
2. Chowdhury AR: Recent advances in heavy metals induced effect on male reproductive function-A retrospective Al Ameen J. Med. Sci. 2009; 2:37-42.
3. Turgut G, Abban S, Turgut and Take G: Effect of overdose zinc on mouse testis and its relation with sperm count and motility. Biol. Trace Elem. Res. 2003; 96:271-278.
4. Veado MARV, Arante IA, Oliveira AH, Almeida MRMG, Miguel RA, Severo MI and Cabaleiro HL: Metal pollution in the environment of minas gerais state-Brazil. Environ. Monit. Assess. 2006; 117:157-172.
5. Kutlubay R, Oguz EO, Can B, Guven MC, Sinik Z and Tuncay OL: Vitamin E protection from testicular damage caused by intraperitoneal aluminium. Int. J. Toxicol. 2007; 26:297-306.
6. Carlsen E, Giwercman A, Keiding N and Skakkebaek NE: Evidence for decreasing quality of semen during past 50 years. Br. Med. J. 1992; 305:609-613.
7. Jensen TK, Sobotka T, Hansen MA, Pedersen AT, Lutz W and Skakkebaek NE: Declining trends in conception rates in recent birth cohorts of native Danish women: A possible role of deteriorating male reproductive health. Int. J. Androl. 2008; 31:81-92.
8. Traina ME, Ade P, Siepi G, Urbani E and Petrelli MG: A review of the effect of pesticide formulations on male fertility. Int. J. Environ. Health Res. 1994; 4:38-47.
9. Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, et al. European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol 2012; 62:324-32.
10. Rani DS, Vanniarajan A, Gupta NJ, Chakravarty B, Singh L, Thangaraj K. A novel missense mutation C11994T in the mitochondrial ND4 gene as a cause of low sperm motility in the Indian subcontinent. Fertil steril 2006; 86:1783-5.
11. Hassani HH, Mohamed WM, Hasan HR, Majeed BJ, Khalf ZS. Heavy Metal Pollution and Men Infertility in Al-Falluja City. Baghdad Sci J 2016; 13:819-28.
12. Mendiola J, Moreno JM, Roca M, Vergara-Juárez N, Martínez-García MJ, García-Sánchez A, et al. Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: a pilot study. Environ Health 2011; 10:6.
13. Corpas I, Castillo M, Marquina D, Benito MJ. Lead intoxication in gestational and lactation periods alters the development of male reproductive organs. Ecotoxicol Environ Saf 2002;53:259-66.
14. Fahim MA, Tariq S, Adeghate E. Vitamin E modifies the ultrastructure of testis and epididymis in mice exposed to lead intoxication. Ann Anat 2013; 195: 272-77.
15. Anjum MR, Madhu P, Reddy KP, Reddy PS. The protective effects of zinc in lead-induced testicular and epididymal toxicity in Wistar rats. Toxicol Ind Health 2017; 33:265-76.
16. P. Gao, S. Liu, W. Ye et al., “Assessment on the occupational exposure of urban public bus drivers to bioaccessible trace metals through resuspended fraction of settled bus dust,” Science of The Total Environment, vol. 508, pp. 37–45, 2015.
17. M. P. Waalkes, “Cadmium carcinogenesis,” Mutation Research, vol. 533, no. 1-2, pp. 107–120, 2003.
18. S. Satarug, S. H. Garrett, M. A. Sens, and D. A. Sens, “Cadmium, environmental exposure, and health outcomes,” Environmental Health Perspectives, vol. 118, no. 2, pp. 182–190, 2010.
19. F. de Souza Predes, M. A. S. Diamante, and H. Dolder, “Testis response to low doses of cadmium in Wistar rats,” International Journal of Experimental Pathology, vol. 91, no. 2, pp. 125–131, 2010.
20. H. Y. Jung, D. W. Seo, C. O. Hong, J. Y. Kim, S. Y. Yang, and K. W. Lee, “Nephroprotection of plantamajoside in rats treated with cadmium,” Environmental Toxicology and Pharmacology, vol. 39, no. 1, pp. 125–136, 2015.
21. M. do Carmo Cupertino, R. D. Novaes, E. C. Santos et al., “Cadmium-induced testicular damage is associated with mineral imbalance, increased antioxidant enzymes activity and protein oxidation in rats,” Life Sciences, vol. 175, pp. 23–30, 2017.
22. M. C. Cupertino, R. D. Novaes, E. C. Santos et al., “Differential Susceptibility of Germ and Leydig Cells to Cadmium- Mediated Toxicity: Impact on Testis Structure, Adiponectin Levels, and Steroidogenesis,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 3405089, 11 pages, 2017.
23. L. Minutoli, A. Micali, A. Pisani et al., “Flavocoxid protects against cadmium-induced disruption of the blood-testis barrier and improves testicular damage and germ cell impairment in mice [corrected],” Toxicological Sciences, vol. 148, no. 1, pp. 311–329, 2015.
24. F. Squadrito, A. Micali, M. Rinaldi et al., “Polydeoxyribonucleotide, an adenosine-A2A receptor agonist, preserves blood testis barrier from cadmium-induced injury,” Frontiers in Pharmacology, vol. 7, 2017.
25. M. W. Hentze, M. U. Muckenthaler, and N. C. Andrews, “Balancing acts: molecular control of mammalian iron metabolism,” Cell, vol. 117, no. 3, pp. 285–297, 2004.
26. D. Y. Ryu, S. J. Lee, D. W. Park, B. S. Choi, C. D. Klaassen, and J. D. Park, “Dietary iron regulates intestinal cadmium absorption through iron transporters in rats,” Toxicology Letters, vol. 152, no. 1, pp. 19–25, 2004.
27. A. Djuric, A. Begic, B. Gobeljic et al., “Oxidative stress, bioelements and androgen status in testes of rats subacutely exposed to cadmium,” Food and Chemical Toxicology, vol. 86, pp. 25– 33, 2015.
28. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, Lee DH, Shioda T, Soto AM, vom Saal FS, Welshons WV, et al: Hormones and endocrine disrupting chemicals: Low dose effects and nonmonotonic dose responses. Endocr Rev 33: 378-455, 2012.
29. Medina MF, Arrieta MC, Villafañe MN, Klyver SMR, Odstrcil IMA and González ME: Early signs of toxicity in testes and sperm of rats exposed to low cadmium doses. Toxicol Ind Health 33: 576-587, 2017.
30. Akinloye O, Arowojolu AO, Shittu OB and Anetor JI: Cadmium toxicity: A possible cause of male infertility in Nigeria. Reprod Biol 6: 17-30, 2006.
31. Luevano J and Damodaran C: A review of molecular events of cadmium induced carcinogenesis. J Environ Pathol Toxicol Oncol 33: 183-194, 2014.
32. Niknafs B, Salehnia M and Kamkar M: Induction and determination of apoptotic and necrotic cell death by cadmium chloride in testis tissue of mouse. J Reprod Infertil 16: 24-29, 2015.
33. De Angelis C, Galdiero M, Pivonello C, Salzano C, Gianfrilli D, Piscitelli P, Lenzi A, Colao A and Pivonello R: The environment and male reproduction: The effect of cadmium exposure on reproductive function and its implication in fertility. Reprod Toxicol 73: 105-127, 2017.
34. Marettoá E, Maretta M and Leqáth J: Toxic effects of cadmium on testis of birds and mammals: A review. Anim Reprod Sci 155: 1-10, 2015.
35. Verqilio CS, Moreira RV, Carvalho CE and Melo EJ: Evolution of cadmium effects in the testis and sperm of the tropical fish Gymnotus carapo. Tissue Cell 47: 132-139, 2015.
36. Yang Q, Li P, Wen Y, Li S, Chen J, Liu X, Wang L and Li X: Cadmium inhibits lysine acetylation and succinylation inducing testicular injury of mouse during development. Toxicol Lett 291: 112-120, 2018.
37. Ali I, Damdimopoulou P, Stenius U, Adamsson A, Mäkelä SI, Åkesson A, Berglund M, Håkansson H and Halldin K: Cadmium induced effects on cellular signaling pathways in the liver of transgenic estrogen reporter mice. Toxicol Sci 127: 66-75, 2012.
38. Schneider SN, Liu Z, Wang B, Miller ML, Afton SE, Soleimani M and Nebert DW: Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: Comparison of uptake, distribution, metal content, and toxicity. Int J Toxicol 33: 14-20, 2014.
39. Hu H, Lu X, Cen X, Chen X, Li F and Zhong S: RNA Seq identifies key reproductive gene expression alterations in response to cadmium exposure. Biomed Res Int 2014: 529271, 2014.
40. Fraga CG. Relevance, essentiality and toxicity of trace elements in human health. Mol Aspects Med 2005;26:235-44.
41. Mehri A, Marjan RF. Trace elements in human nutrition: A review. Int J Med Invest 2013;2:115-28.
42. Apgar J. Zinc and reproduction: An update. J Nutr Biochem 1992;3:266-78.
43. Egwurugwu JN, Ifedi CU, Uchefuna RC, Ezeokafor EN, Alagwu EA. Effects of zinc on male sex hormones and semen quality in rats. Niger J Physiol Sci 2013;28:17-22.
44. Li Y, Wu J, Zhou W, Gao E. Effects of manganese on routine semen quality parameters: Results from a population-based study in China. BMC Public Health 2012;12:919.
45. Keen CL, Zidenberg-Cherr S, Lo¨nnerdal B. Nutritional and toxicological aspects of manganese intake: An overview. In: Mertz W, Aternathy CO, Olin SS, editors. Risk Assessment of Essential Elements. Washington, DC: International Life Sciences Institute; 1994. p. 221-35.
46. Godatvar PR. Shukra: A clinical and experimental study on therole of Svarna Bhasma in normozoospermia. MD Thesis Submitted to Gujarat Ayurved University. Jamnagar: Gujarat Ayurved University; 1995.
47. Hamad AR, Al-Daghistani HI, Shquirat WD, Abdel-Dayem M, Al-Swaifi M. Trace element levels in seminal plasma which associated with sperm quality in fertile and infertile men. J Reprod Infertil 2014;5:14-22.
48. Yokoi K, Uthus EO, Nielsen FH. Nickel deficiency diminishes sperm quantity and movement in rats. Biol Trace Elem Res 2003;93:141-54.
49. Marzec-Wróblewska U, Kaminski P, Lakota P. Influence of chemical elements on mammalian spermatozoa. Folia Biol (Praha) 2012;58:7-15.
50. Oura C, Toshimori K. Ultrastructural studies on the fertilization ofmammalian gametes. Int Rev Cytol 1990;122:105-51.
51. Barltrop D, Khoo HE. The influence of nutritional factors on leadabsorption. Postgrad Med J 1975;51:795-800.
52. Nawal KA, Ula AK, Ban TS. Protective influence of zinc on reproductiveparameters in male rat treated with cadmium. Am J Med Med Sci2015;5:73-81.
53. Imafidon CE, Akomolafe RO, Sanusi AA, Ogundipe OJ, Olukiran OS, Ayowole OA. Polyphenol-rich extract of Vernonia amygdalina (Del.)leaves ameliorated cadmium-induced alterations in feeding patternand urine volume of male Wistar rats. J Intercult Ethnopharmacol2015;4:284-92.
54. IPCS, (International Programme on Chemical Safety). Cadmium -Environmental Aspects. Geneva: World Health Organization; 1992.p.135.
55. WHO, (World Health Organization). Preventing Disease throughHealthy Environments, Exposure to Cadmium: A Major Public Health Concern. Geneva, Switzerland: WHO; 2010.
56. Lewis GP, Coughlin LL, Jusko WJ, Hartz S. Contribution of cigarettesmoking to cadmium accumulation in man. Lancet 1972;1:291-2.
57. Järup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Healtheffects of cadmium exposure – a review of the literature and a riskestimate. Scand J Work Environ Health 1998;24 Suppl 1:1-51.
58. Bernard A. Renal dysfunction induced by cadmium: Biomarkers ofcritical effects. Biometals 2004;17:519-23.
59. Nordberg G, Nogawa K, Nordberg M, Friberg L. Cadmium. In:Handbook on Toxicology of Metals. New York: Academic Press;2007. p. 65-78.
60. Prozialeck WC, Edwards JR, Woods JM. The vascular endotheliumas a target of cadmium toxicity. Life Sci 2006;79:1493-506.
61. Goering PL, Waalkes MP, Klaasen CD. Toxicology of cadmium.Handbook of Experimental Pharmacology; Toxicology of Metals,Biochemical Effects. Vol. 115. New York: Springer-Verlag; 1994.p.189-214.
62. Klaassen CD, Liu J, Choudhuri S. Metallothionein: An intracellularprotein to protect against cadmium toxicity. Annu Rev PharmacolToxicol 1999;39:267-94.
63. Stohs SJ, Bagchi D, Hassoun E, Bagchi M. Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol 2001;20:77-88.
64. Nagma M, Nagma JA, Jamal S, Abdur R. Protective effect of rutinagainst cadmium induced hepatotoxicity in Swiss Albino Mice.J Pharmacol Toxicol 2012;7:150-7.
65. Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metalions. Free Radic Biol Med 1995;18:321-36.
66. Buzzle-Side Effects of Polyphenols. August, 24; 2010. Available from:http://www.buzzle.com/articles/polyphenols-side-effects.html. [Last accessed on 2016 Mar 22].
67. Doaa El-Nager M, Badr AA. Effect of corn oil, flax seed oil and black seed oil on testicular damage induced by lead acetate in Albino Mice: A histological study. Pak J Zool 2013;45:1083-9.
68. El?bieta Bonda, Tadeusz W?ostowski & Alicja Krasowska, Testicular toxicity induced by dietary cadmium is associated with decreased testicular zinc and increased hepatic and renal metallothionein and zinc in the bank vole (Clethrionomys glareolus), Biometals, (2004), volume 17, pages615–624.
69. Ragan HA, Mast TJ. Cadmium inhalation and male reproductive toxicity. Rev Environ Contam Toxicol 1990;114:1-22.
70. Al-Attar AM. Antioxidant effect of vitamin E treatment on some heavy metals-induced renal and testicular injuries in male mice. Saudi J Biol Sci 2011;18:63-72.
71. Geoffroy-Siraudin C, Perrard MH, Ghalamoun-Slaimi R, Ali S, Chaspoul F, Lanteaume A, et al. Ex-vivo assessment of chronic toxicity of low levels of cadmium on testicular meiotic cells. Toxicol Appl Pharmacol 2012;262:238-46.
72. Lukac N, Massanyi P, Zakrzeweski M, Toman R, Cigankova V, Stawarz R. Cobalt induced alterations in hamster’s testes in vivo. J Environ Sci Health Tox Hazard Subst Environ Eng 2007;42:389-92.
73. Elbetieha A, Al-Tthani AS, Al-Tthani RK, Darmani H, Owais W. Effect of chronic exposure to cobalt chloride on the fertility and testes in mice. J Appl Biol 2008;2:1-6.
74. Al-Attar AM. Antioxidant effect of vitamin E treatment on some heavy metals-induced renal and testicular injuries in male mice. Saudi J Biol Sci 2011;18:63-72.
75. Ponnapakkam TP, Bailey KS, Graves KA, Iszard MB. Assessment of male reproductive system in the CD-1 mice following oral manganese exposure. Reprod Toxicol 2003;17:547-51.
76. Slivkova J, Popelkova M, Massanyi P, Toporcerova S, Stawarz R, Formicki G, et al. Concentration of trace elements in human semen and relation to spermatozoa quality. J Environ Sci Health A Tox Hazard Subst Environ Eng 2009;44:370-5.
77. Zhai XW, Zhang YL, Qi Q, Bai Y, Chen XL, Jin LJ, et al. Effects of molybdenum on sperm quality and testis oxidative stress. Syst Biol Reprod Med 2013;59:251-5.
78. Pandey R, Srivastava SP. Spermatotoxic effects of nickel in mice. Bull Environ Contam Toxicol 2000;64:161-7.
79. Mocevic E, Specht IO, Marott JL, Giwercman A, Jönsson BA, Toft G, et al. Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: A cross-sectional study. Asian J Androl 2013;15:97-104.
80. Choy CM, Lam CW, Cheung LT, Briton-Jones CM, Cheung LP, Haines CJ. Infertility, blood mercury concentrations and dietary seafood consumption: A case-control study. BJOG 2002;109:1121-5.
81. Heath JC, Abdelmageed Y, Braden TD, Goyal HO. The effects of chronic ingestion of mercuric chloride on fertility and testosterone levels in male Sprague Dawley rats. J Biomed Biotechnol 2012;2012:815186.
82. Massanyi P, Zemanova J, Makarevich A, Chrenek P, Cigánková V, Toman R, et al. Effect of nickel administration in vivo on the testicular structure in male mice. Acta Vet Brno 2007;76:223-9.
83. Pandey R, Kumar R, Singh SP, Saxena DK, Srivastava SP. Male reproductive effect of nickel sulphate in mice. Biometals 1999;12:339-46.
84. Danadevi K, Rozati R, Reddy PP, Grover P. Semen quality of Indian welders occupationally exposed to nickel and chromium. Reprod Toxicol 2003;17:451-6.
85. Zhao LL, Ru YF, Liu M, Tang JN, Zheng JF, Wu B, Gu YH, Shi HJ. Reproductive effects of cadmium on sperm function and early embryonic development in vitro. PLoS One. 2017 Nov 2;12(11):e0186727. doi: 10.1371/journal.pone.0186727. PMID: 29095856; PMCID: PMC5667747.
86. Cedric Pisani, Sebastien Voisin, Karim Arafah, Philippe Durand, Marie-Hélène Perrard, et al.. Ex Vivo Assessment of Testicular Toxicity Induced by Carbendazim and Iprodione, Alone or in a Mixture. Altex-alternatives to animal experimentation, 2016, 33 (4), pp.393–413. ff10.14573/altex.1601253ff. ffhal-01444080f
87. Shail K Chaube, In Vivo and In Vitro Studies on Nickel Induced Reproductive Toxicity and the Protective Role of Melatonin. Biology of Reproduction 83(1):114 · November 2010, DOI: 10.1093/biolreprod/83.s1.289
88. Lafuente A, Cano P, Esquifino A. Are cadmium effects on plasma gonadotropins, prolactin, ACTH, GH and TSH levels, dose-dependent? Biometals. 2003;16:243–250.
89. Milan Chandel, Gyan Chand Jain, Toxic eff ects of transition metals on male reproductive system: A review, J Environ Occup Sci, Oct-Dec 2014, Vol 3, Issue 4, 204-13.
90. Corpas I, Castillo M, Marquina D. And Benito MJ: Lead Intoxication in Gestational and Lactation Periods Alters the Development of Male Reproductive Organs. Ecotoxicology and Environmental Safety. 2001; 53:259-266.
91. Shan G, Tang T. And Zhang X: The Protective Effect of Ascorbic Acid and Thiamine Supplementation against Damage Caused by Lead in the Testes of Mice. J Huazhong Univ Sci Technol Med Sci. 2009; 29:68-72.
92. Batra N, Nehru B, Bansal MP: Influence of lead and zinc on rat male reproduction at biochemical and histopathological levels. Journal of Applied Toxicology. 2001; 21, 507–512.
93. Batra N, Nehru B and Bansal MP: Reproductive potential of male portan rats exposed to various levels of lead regard to Zinc status. Br. J. Nutr. 2004; 91, 1887-1891.
94. Adhikari N, Sinha N, Narayan R and Saxena DK: Lead- induced cell death in testes of young rats. J. Applied Toxicol. 2001; 21, 275-277.
95. Kissel H et al.: Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signalling in spermatogenesis and oogenesis without affecting other kit responses. EMBO J. 2000; 19, 1312-1326.
96. Beckman, L. 1978. The Ronnskar smelter-occupational and environmental effects in and around a polluting industry in northern Sweden. Ambio. 7:226–231.
97. Hopenhayn-Rich, C., I. Hertz-Picciotto, S. Browning, C. Ferreccio, and C. Peralta. 1999. Reproductive and developmental effects associated with chronic arsenic exposure. Ars. Expos. Hlth. Eff. 3:151–164.
98. Danielsson, B. R., L. Dencker, A. Lindgreen, and H. Tjalve. 1984. Accumulation of toxic metals in male reproductive organs. Arch. Toxicol. Supp. 7: 177–180.
99. Pant, N., R. Kumar, R. C. Murthy, and S. P. Srivastava. 2001. Male reproductive effect of arsenic in mice. BioMetals. 14:113–117.
100. Sarkar, M., G. R. Chaudhuri, A. Chattopadhyay, and N. M. Biswas. 2003. Effect of sodium arsenite on spermatogenesis, plasma gonadotrophins and testosterone in rats. Asian J. Androl. 5:27–31.
101. Xiao Sun, Siwen Li, Ying He, Hongjing Zhao, Yu Wang, Xiangwei Zeng, and Mingwei Xing, Physiology and reproduction, Arsenic-induced testicular toxicity in Gallus gallus: Expressions of inflammatory cytokines and heat shock proteins, 2017, Poultry Science 96:3399–3406, http://dx.doi.org/10.3382/ps/pex073
102. Sanghamitra Sarkar, Hazra J., Upadhyay S. N., Singh R. K. and Amal Roy Chowdhury, Arsenic induced toxicity on testicular tissue of mice, Indian J Physiol Pharmacol 2008; 52(1) 84–90
103. Viviane G. S. Mouro ,1 Ana L. P. Martins,1 Janaina Silva,1 Tatiana P. Menezes, Marcos L. M. Gomes,2 Juraci A. Oliveira,1 Fabiana C. S. A. Melo , and Sérgio L. P. Matta, Cadmium (Cd) is a nonessential metal that can contaminate, Subacute Testicular Toxicity to Cadmium Exposure, Intraperitoneally and Orally, Hindawi , Oxidative Medicine and Cellular Longevity, Volume 2019, Article ID 3429635, 14 pages, https://doi.org/10.1155/2019/3429635
104. Erica R. Siu, Dolores D. Mruk, Catarina S. Porto, and C. Yan Cheng, Cadmium-induced Testicular Injury, Toxicol Appl Pharmacol. 2009 August 1; 238(3): 240–249. doi:10.1016/j.taap.2009.01.028.
105. Hideaki Shimada, Rika Narumi, Masaaki Nagano, Akira Yasutake, Michael P. Waalkes, Yorishige Imamura, Strain difference of cadmium-induced testicular toxicity in inbred Wistar–Imamichi and Fischer 344 rats, Arch Toxicol. 2009 July ; 83(7): 647–652. doi:10.1007/s00204-009-0442-y.
106. Christian Eseigbe Imafidon, Olatoye Taiwo Risikat, Bamidele Funminiyi Samuel, Ojo Opeyemi Esther, Ademoye Kehinde Aderonke, Cadmium-Induced Testicular Toxicity, Oxidative Stress and Histopathology in Wistar Rats: Sustained Effects of Polyphenol-Rich Extract of Vernonia Amygdalina (Del.) Leaf, J Interdiscip Histopathol. 2016; 4(3): 54-62. doi: 10.5455/jihp.20160618041629
107. Yaping Ren, Wenhua Shao, Lijun Zuo, Wei Zhao, Haizhang Qin, Yingjie Hua, Dejie Lu, Chao Mi, Sien Zeng and Liao Zu, Mechanism of cadmium poisoning on testicular injury in mice, Oncology Letters, 18: 1035-1042, 2019
108. Amany Ramah, Ragab M. EL-shwarby, Nabila M. A., Elham A. El-shewey, The effect of lead toxicity on male albino rats reproduction with ameliorate by vitamin E and pumpkin seeds oil, Benha veterinary medical journal, vol. 28, no. 1:43?52, march 2015.
109. Viviane Gorete Silveira Mouro, Verônica Andrade Siman, Janaína da Silva , Fernanda Carolina Ribeiro Dias, Eduardo Medeiros Damasceno, Marli do Carmo Cupertino, Fabiana Cristina Silveira Alves de Melo, Sérgio Luis Pinto da Matta , Biol Trace Elem Res, Cadmium-Induced Testicular Toxicity in Mice: Subacute and Subchronic Route-Dependent Effects. 2020 Feb;193(2):466-482. doi: 10.1007/s12011-019-01731-5. Epub 2019 Apr 27.
110. Siu, R Erica & Mruk, Dolores & Porto, Catarina & Cheng, C. (2009). Cadmium-induced Testicular Injury. Toxicology and applied pharmacology. 238. 240-9. 10.1016/j.taap.2009.01.028.
111. Christian Eseigbe Imafidon, Olatoye Taiwo Risikat, Bamidele Funminiyi Samuel, Ojo Opeyemi Esther, Ademoye Kehinde Aderonke Cadmium-induced testicular toxicity, oxidative stress and histopathology in Wistar rats: Sustained effects of polyphenol-rich extract of Vernonia amygdalina (del.) leaf, Journal of Interdisciplinary Histopathology, 2016; 4(3): 54-62 www.scopmed.orgDOI: 10.5455/jihp.2016061804162954
112. U. Garu, R. Sharma and I. Barber, Effect of lead toxicity on developing testis of mice, IJPSR, 2011; Vol. 2(9): 2403-2407
113. Suna Kalender, Fatma Gokce Uzun, Filiz Demir, Meltem Uzunhisarc?kl?, Ayse Aslanturk, Mercuric chloride-induced testicular toxicity in rats and the protective role of sodium selenite and vitamin E,  Food Chem Toxicol, 2013 May;55:456-62.  doi: 10.1016/j.fct.2013.01.024. Epub 2013 Jan 29.
114. Hatem Moussa, Lamia Hachfi, Mouni Trimeche, Mohamed Fadhel Najjar, Accumulation of mercury and its effects on testicular functions in rats intoxicated orally by methylmercury, Andrologia 43(1):23-7 · February 2011 with 105 Reads , DOI: 10.1111/j.1439-0272.2009.01003.x
115. Azarnia Mahnaz, Sanaie-Mehr A., Mercury induces testicular damage protected by zinc in mice, iranian journal of biology,   2003 , Volume 15 , Number 3; Page(s) 16 To 24.