This article examines the environmental factor-induced oxidative stress (OS) and their effects on male reproductive and sexual health. There are several factors that induce OS, i.e. radition, metal contamination, xenobiotic compounds, and cigarette smoke and lead to cause toxicity in the cells through metabolic or bioenergetic processes. These environmental factors may produce free radicals and enhance the reactive oxygen species (ROS). Free radicals are molecules that include oxygen and disbalance the amount of electrons that can create major chemical chains in the body and cause oxidation. Oxidative damage to cells may impair male fertility and lead to abnormal embryonic development. Moreover, it does not only cause a vast number of health issues such as ageing, cancer, atherosclerosis, insulin resistance, diabetes mellitus, cardiovascular diseases, ischemia-reperfusion injury, and neurodegenerative disorders but also decreases the motility of spermatozoa while increasing sperm DNA damage, impairing sperm mitochondrial membrane lipids and protein kinases. This chapter mainly focuses on the environmental stressors with further discussion on the mechanisms causing congenital impairments due to poor sexual health and transmitting altered signal transduction pathways in male gonadal tissues.

Animal Production Division ICAR Research Complex for NEH Region Indian Council of Agricultural Research Umiam Meghalaya India

Department of Animal Morphology Physiology and Genetics Faculty of AgriSciences Mendel University in Brno Brno Czech Republic

Department of Animal Physiology Faculty of Biotechnology and Food Sciences Slovak University of Agriculture in Nitra Nitra Slovak Republic

Department of Applied Physics School of Science Aalto University Espoo Finland

Department of Biotechnology School of Engineering and Technology Sharda University Greater Noida India

Department of Botany Acharya Prafulla Chandra College New Barrackpore Kolkata West Bengal India

Department of Life Science and Bioinformatics Assam University Silchar India

Department of Zoology Acharya Prafulla Chandra College New Barrackpore Kolkata West Bengal India

Department of Zoology Bajkul Milani Mahavidyalaya Purba Medinipur West Bengal India

Department of Zoology Egra SSB College Purba Medinipur West Bengal India

Department of Zoology Gauhati University Guwahati India

School of Health Sciences and Technology UPES University Dehradun Uttarakhand India

See more in PubMed

Acharya UR, Mishra M, Patro J, Panda MK. Effect of vitamins C and E on spermatogenesis in mice exposed to cadmium. Reprod Toxicol. 2008;25:84–8. https://doi.org/10.1016/j.reprotox.2007.10.004 . DOI

Adesina SE, Kang BY, Bijli KM. Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med. 2015;87:36–47. DOI

Ahmad HI, Majeed MBB, Jabbar A, Arif R, Afzal G. Reproductive toxicity of arsenic: what we know and what we need to know? Environ Health. 2020:1–14. https://doi.org/10.5772/intechopen.95379 .

Aitken JR, Koppers AJ. Apoptosis and DNA damage in human spermatozoa. Asian J Androl. 2011;13:36–42. DOI

Akinloye O, Arowojolu AO, Shittu OB, Anetor JI. Cadmium toxicity: a possible cause of male infertility in Nigeria. Reprod Biol. 2006;6:17–30.

Alahmar AT. Role of oxidative stress in male infertility: an updated review. J Hum Reprod Sci. 2019;12(1):4–18. DOI

Al-Damegh MA. Stress-induced changes in testosterone secretion in male rats: role of oxidative stress and modulation by antioxidants. Open J Anim Sci. 2014;4(2):70–8. DOI

Aldred AR, Grimes A, Schreiber G, Mercer JF. Rat ceruloplasmin. Molecular cloning and gene expression in liver, choroid plexus, yolk sac, placenta, and testis. J Biol Chem. 1987;262:2875–8. DOI

Alvarez JG, Storey BT. Differential incorporation of fatty acids into and peroxidative loss of fatty acids from phospholipids of human spermatozoa. Mol Reprod Dev. 1995;42:334–46. DOI

Aminjan HH, Abtahi SR, Hazrati E, Chamanara M, Jalili M, Paknejad B. Targeting of oxidative stress and inflammation through ROS/NF-kappa B pathway in phosphine-induced hepatotoxicity mitigation. Life Sci. 2019;232:116607. https://doi.org/10.1016/j.lfs.2019.116607 . DOI

Arita A, Costa M. Epigenetics in metal carcinogenesis: nickel, arsenic, chromium and cadmium. Metallomics. 2009;1:222–8. DOI

Arredondo M, Nunez MT. Iron and copper metabolism. Mol Aspects Med. 2005;26:313–27. DOI

Aruldhas MM, Subramanian S, Sekar P, Vengatesh G, Chandrahasan G, Govindarajulu P, Akbarsha M. Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress: study in a non-human primate (Macaca radiata Geoffroy). Hum Reprod. 2005;2005(20):2801–13. DOI

Ashraf MW. Levels of heavy metals in popular cigarette brands and exposure to these metals viasmoking. Sci. World J. 2012; ID 729430.

Aydemir B, Kiziler AR, Onaran I, Alici B, Ozkara H, Akyolcu MC. Impact of Cu and Fe concentrations on oxidative damage in male infertility. Biol Trace Elem Res. 2006;112:193–203. DOI

Banafsheh AA, Sirous G. Studies on oxidants and antioxidants with a brief glance at their relevance to the immune system. Life Sci. 2016;146:163–173. https://doi.org/10.1016/j.lfs.2016.01.014

Basant KP, Treasaden IH, Cocchi M, Tsaluchidu S, Tonello L, Ross BM. A comparison of oxidative stress in smokers and non-smokers: an in vivo human quantitative study of n-3 lipid peroxidation. BMC Psychiatry. 2008;8(Suppl 1):S4.

Bertolero F, Pozzi G, Sabbioni E, Saffiotti U. Cellular uptake and metabolic reduction of pentavalent to trivalent arsenic as determinants of cytotoxicity and morphological transformation. Carcinogenesis. 1987;8:803–8. DOI

Bertram M, Graedel TE, Rechberger H, Spatari S. The contemporary European copper cycle: waste management subsystem. Ecol Econ. 2002;42:3–57. DOI

Betka M, Callard GV. Stage-dependent accumulation of cadmium and induction of metallothionein-like binding activity in the testis of the Dogfish shark Squalus acanthias. Biol Reprod. 1999;60:14–22. DOI

Bisht S, Dada R. Oxidative stress: major executioner in disease pathology, role in sperm DNA damage and preventive strategies. Front Biosci (Schol Ed). 2017;9:420–47. DOI

Biswas S, Talukder G, Sharma A. Prevention of cytotoxic effects of arsenic by short-term dietary supplementation with selenium in mice in vivo. Mutat Res. 1999;441:155–60. DOI

Bizarro P, Acevedo S, Nino-Cabrera G, Mussali-Galante P, Pasos F, Avila- Costa MR. Ultrastructural modifications in the mitochondrion of mouse Sertoli cells after inhalation of lead, cadmium or lead-cadmium mixture. Reprod Toxicol. 2003;17:561–6. https://doi.org/10.1016/S0890-6238(03)00096-0 . DOI

Bjørklund G, Chirumbolo S, Dadar M, Pivina L, Lindh U, Butnariu M, Aaseth J. Mercury exposure and its effects on fertility and pregnancy outcome. Basic Clin Pharmacol Toxicol. 2019;125(4):317–327.

Blanco A, Moyano R, Vivo J, Flores-Acuna R, Molina A, Blanco C. Quantitative changes in the testicular structure in mice exposed to low doses of cadmium. Environ Toxicol Pharmacol. 2007;23:96–101. https://doi.org/10.1016/j.etap.2006.07.008 . DOI

Blanco A, Moyano R, Molina López AM, Blanco C, Flores-Acuña R, García-Flores JR, … Monterde JG. Preneoplastic and neoplastic changes in the Leydig cells population in mice exposed to low doses ofcadmium. Toxicol Ind Health. 2010;26(8):451–457.

Bogdan C, Daniela M, Maria G, Andrey VK, Jakob T, Vera R, Anton A. Oxidative stress and volatile organic compounds: interplay in pulmonary, cardio-vascular, digestive tract systems and cancer. Open Chem. 2015;13:1–11.

Bonde JP, Giwercman A. Environmental xenobiotics and male reproductive health. Asian J Androl. 2014;16(1):3–4. DOI

Bonefeld-Jørgensen EC, Ghisari M, Wielsøe M, Bjerregaard-Olesen C, Kjeldsen LS, Long M. Biomonitoring and hormone-disrupting effect biomarkers of persistent organic pollutants in vitro and ex vivo. Basic Clin Pharmacol Toxicol. 2014;115(1):118–28. DOI

Bonnet S, Boucherat O. The ROS controversy in hypoxic pulmonary hypertension revisited. Eur Respir J. 2018;51:1800276. https://doi.org/10.1183/13993003.00276-2018 . DOI

Braganza JM, Dormandy TL. Micronutrient therapy for chronic pancreatitis: rationale and impact. JOP. 2010;11:99–112.

Brook RD, Franklin B, Cascio W. Air pollution and cardiovascular disease. Circulation. 2004;109:2655–71. DOI

Bruno RS, Traber MG. Vitamin E biokinetics, oxidative stress and cigarette smoking. Pathophysiology. 2006;13:143–9. DOI

Cescon M, Chianese R, Tavares RS. Environmental impact on male (In)Fertility via epigenetic route. J Clin Med. 2020;9(8):2520. DOI

Chan D, Delbes G, Landry M, Robaire B, Trasler JM. Epigenetic alterations in sperm DNA associated with testicular cancer treatment. Toxicol Sci. 2012;125:532–43. DOI

Chen H, Zhao HX, Huang XF, Chen GW, Yang ZX, Sun WJ, Tao MH, Yuan Y, Wu JQ, Sun F, Dai Q, Shi HJ. Does high load of oxidants in human semen contribute to male factor infertility? Antioxid Redox Signal. 2012;16(8):754–9. DOI

Chen Y, Chang YK, Su YR, Chang HC. Ambient sulphur dioxide could have an impact on testicular volume from a observational study on a population of infertile male. BMC Urol. 2020;20:149. DOI

Cheng TF, Choudhuri S, Muldoon-Jacobs K. Epigenetic targets of some toxicologically relevant metals: a review of the literature. J Appl Toxicol. 2012;32:643–53. DOI

Chirino YI, Sánchez-Pérez Y, Osornio-Vargas AR. PM10 impairs the antioxidant defense system and exacerbates oxidative stress driven cell death. Toxicol Lett. 2010;193(3):209–16. DOI

Chowdhury AR, Vachhrajani KD, Chatterjee BB. Inhibition of 3 beta-hydroxy-delta 5-steroid dehydrogenase in rat testicular tissue by mercuric chloride. Toxicol Lett. 1985;27:45–9. DOI

Cupertino MC, Novaes RD, Santos EC, Neves AC, Silva E, Oliveira JA. Differential susceptibility of germ and Leydig cells to cadmium-mediated toxicity: impact on testis structure, adiponectin levels, and steroidogenesis. Oxid Med Cell Longev. 2017;2017:3405089. https://doi.org/10.1155/2017/3405089 . DOI

Dabestani R, Ivanov IN. A compilation of physical, spectroscopic and photophysical properties of polycyclic aromatic hydrocarbons. Photochem Photobiol. 1999;70:10–34.

Damian GD, Elizabeth AM, Judith MH, Ruth R. Drug-induced oxidative stress and toxicity. J Toxicol. 2012;2012:1–13. DOI

Danielsson BR, Dencker L, Lindgren A, Tjalve H. Accumulation of toxic metals in male reproduction organs. Arch Toxicol Suppl. 1984;7:177–80. DOI

De-Luca MN, Colone C, Gambioli G, Stringaro A, Unfer V. Oxidative stress and male fertility: role of antioxidants and inositols. Antioxidants. 2021;10(8):1283. https://doi.org/10.3390/antiox10081283 . DOI

Deng J, Guo H, Cui H, Fang J, Zuo Z, Deng J. Oxidative stress and inflammatory responses involved in dietary nickel chloride (NiCl DOI

Dogan MV, Shields B, Cutrona C. The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women. BMC Genomics. 2014;15(1):151. DOI

Donaldson K, Stone V, Clouter A, Renwick L, MacNee W. Ultrafine particles. Occup Environ Med. 2001;58(3):211–216.

Donkin I, Barrès R. Sperm epigenetics and influence of environmental factors. Mol Metab. 2018;14(2018):1–11. DOI

Doumouchtsis KK, Doumouchtsis SK, Doumouchtsis EK, Perrea DN. The effect of lead intoxication on endocrine functions. J Endocrinol Invest. 2009;32:175–83. DOI

Dutta S, Sengupta P, Slama P, Roychoudhury S. Oxidative stress, testicular inflammatory pathways and male reproduction. Int J Mol Sci. 2021;2021(22):10043. https://doi.org/10.3390/ijms221810043 . DOI

Elmallah MIY, Elkhadragy MF, Al-Olayan EM, Abdel Moneim AE. Protective effect of Fragaria ananassa crude extract on cadmium induced lipid peroxidation, antioxidant enzymes suppression, and apoptosis in rat testes. Int J Mol Sci. 2017;18:957. https://doi.org/10.3390/ijms18050957 . DOI

Ewa LG, Anna P. Endocrine-disrupting chemicals: some actions of POPs on female reproduction. Int J Endocrinol. 2013;(Special issue):1–9.

Fabiano C, Tezotto T, Favarin JL, Polacco JC, Mazzafera P. Essentiality of nickel in plants: a role in plant stresses. Front Plant Sci. 2015;6:754. DOI

Farhat SCL, Silva CA, Orione MM. Air pollution in autoimmune rheumatic diseases: a review. Autoimmun Rev. 2011;11:14–21. DOI

Figa-Talamanca I, Hatch MC. Reproduction and the workplace: what we know end where we go from here. Int J Occup Med Tox. 1994;3:279–303.

Francesca P, Marcello S. Environmental impact on DNA methylation in the germline: state of the art and gaps of knowledge. Biomed Res Int. 2015;15:1–23.

Franco R, Panayiotidis MI. Environmental toxicity, oxidative stress, human disease and the ‘black box’ of their synergism: how much have we revealed? Mutat Res. 2009;674:1–2. DOI

Gaido KW, Wierda D. Suppression of bone marrow stromal cell function by benzene and hydroquinone is ameliorated by indomethacin. Toxicol Appl Pharmacol. 1987;89:378–90. DOI

Gibb S. Toxicity testing in the 21st century: a vision and a strategy. Reprod Toxicol. 2008;25:136–8. DOI

Gibb HJ, Lees PS, Pinsky PF, Rooney BC. Lung cancer among workers in chromium chemical production. Am J Ind Med. 2000;38:115–26. DOI

Goodrich JM, Basu N, Franzblau A, Dolinoy DC. Mercury biomarkers and DNA methylation among Michigan dental professionals. Environ Mol Mutagen. 2013;54:195–203. DOI

Govindarajan B, Klafter R, Miller MS, Mansur C, Mizesko M, Bai X, LaMontagne K Jr, Arbiser JL. Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase. Mol Med. 2002;8:1–8. DOI

Govindaraju M, Shekar HS, Sateesha SB, Vasudeva RP, Sambasiva RKR, Rao KSJ, Rajamma AJ. Copper interactions with DNA of chromatin and its role in neurodegenerative disorders. J Pharm Anal. 2013;3(5):354–9. https://doi.org/10.1016/j.jpha.2013.03.003 . Epub 2013 Apr 28. DOI

Gruber DR, Toner JJ, Miears HL, Shernyukov AV, Kiryutin AS, Lomzov AA, Endutkin AV, Grin IR, Petrova DV, Kupryushkin MS, Yurkovskaya AV, Johnson EC, Okon M, Bagryanskaya EG, Zharkov DO, Smirnov SL. Oxidative damage to epigenetically methylated sites affects DNA stability, dynamics and enzymatic demethylation. Nucleic Acids Res. 2018;46(20):10827–39.

Gurung P, Yetiskul E, Jialal I. Physiology, male reproductive system. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. PMID: 30860700.

Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 4th ed. New York: Oxford University Press; 2007.

Hardneck F, de Villiers C, Maree L. Effect of copper sulphate and cadmium chloride on non-human primate sperm function in vitro. Int J Environ Res Public Health. 2021;2021(18):6200. https://doi.org/10.3390/ijerph18126200 . DOI

Harlev A, Agarwal A, Gunes SO, Shetty A, du Plessis SS. Smoking and male infertility: an evidence-based review. World J Mens Health. 2015;33(3):143–60. DOI

Hauser R, Sergeyev O, Korrick S, Lee MM, Revich B, Gitin E. Association of blood lead levels with onset of puberty in Russian boys. Environ Health Perspect. 2008;116:976–80. DOI

Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr. 2002;22:439–58. DOI

Hiroshi CI, Shiraishi H, Nakagawa M, Takamura N. Combined impact of pesticides and other environmental stressors on animal diversity in irrigation ponds. PLoS One. 2020;15(7):e0229052. https://doi.org/10.1371/journal.pone.0229052 . p. 1–20. DOI

Holme JA, Brinchmann BC, Refsnes M, Låg M, Øvrevik J. Potential role of polycyclic aromatic hydrocarbons as mediators of cardiovascular effects from combustion particles. Environ Health. 2019;18:74. https://doi.org/10.1186/s12940-019-0514-2 . DOI

Hong YS, Song KH, Chung JY. Health effects of chronic arsenic exposure. J Prev Med Public Health. 2014;47(5):245–52. DOI

Hu H, Lu X, Cen X, Chen X, Li F, Zhong S. RNA-Seq identifies key reproductive gene expression alterations in response to cadmium exposure. Biomed Res Int. 2014;2014:529271. https://doi.org/10.1155/2014/529271 . DOI

Huang YL, Tseng WC, Cheng SY, Lin TH. Trace elements and lipid peroxidation in human seminal plasma. Biol Trace Elem Res. 2000;76:207–15. DOI

Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic exposure and toxicology: a historical perspective. Toxicol Sci. 2011;123(2):305–32. DOI

Hymie A, Zul M. Understanding stress: characteristics and caveats. Alcohol Res Health. 1999;23(4):241–9.

Hyun-Wook R, Dong Hoon L, Hye-Rim W, Kyeong HK, Yun-Jeong S, So-Hee K. Influence of toxicologically relevant metals on human epigenetic regulation. Toxicol Res. 2015;31(1):1–9. DOI

James MS, Phillip AW. Oxidative stress from environmental exposures. Curr Opin Toxicol. 2018;7:60–6. DOI

Jana K, Jana S, Samanta PK. Effects of chronic exposure to sodium arsenite on hypothalamo-pituitary-testicular activities in adult rats: possible an estrogenic mode of action. Reprod Biol Endocrinol. 2006;4:9. DOI

Ji W, Yang L, Yu L, Yuan J, Hu D, Zhang W, Yang J, Pang Y, Li W, Lu J, Fu J, Chen J, Lin Z, Chen W, Zhuang Z. Epigenetic silencing of O6-methylguanine DNA methyltransferase gene in NiS-transformed cells. Carcinogenesis. 2008;29:1267–75. DOI

Kachur AV, Koch CJ, Biaglow JE. Mechanism of copper-catalyzed oxidation of glutathione. Free Radic Res. 1998;28(3):259–69. DOI

Kamisaki Y, Wada K, Nakamoto K, Kishimoto Y, Ashida K, Itoh T. Substances in the aqueous fraction of cigarette smoke inhibit lipid peroxidation in synaptosomes of rat cerebral cortex. Biochem Mol Biol Int. 1997;42:1–10.

Kang J, Lin C, Chen J, Liu Q. Copper induces histone hypoacetylation through directly inhibiting histone acetyl transferase activity. Chem Biol Interact. 2004;148:115–23. DOI

Karavelas T, Mylonas M, Malandrinos G, Plakatouras JC, Hadjiliadis N, Mlynarz P, Kozlowski H. Coordination properties of Cu(II) and Ni(II) ions towards the C-terminal peptide fragment -ELAKHA- of histone H2B. J Inorg Biochem. 2005;99:606–15. DOI

Kelsey KT, Rytel M, Dere E. Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to agent orange. Environ Health. 2019;18:91. DOI

Kile ML, Baccarelli A, Hoffman E. Prenatal arsenic exposure and DNA methylation in maternal and umbilical cord blood leukocytes. Environ Health Perspect. 2012;120(7):1061–6. DOI

Kim H, Kim YD, Lee H, Kawamoto T, Yang M, Katoh T. Assay of 2-naphthol in human urine by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1999;734(2):211–7. DOI

Koestler DC, Avissar-Whiting M, Houseman EA, Karagas MR, Marsit CJ. Differential DNA methylation in umbilical cord blood of infants exposed to low levels of arsenic in utero. Environ Health Perspect. 2013;121(8):971–7. DOI

Koul A, Bhatia V, Bansal MP. Effect of alpha-tocopherol on pulmonary antioxidant defence system and lipid peroxidation in cigarette smoke inhaling mice. BMC Biochem. 2001;2:14–8. DOI

Krezel A, Maret W. Dual nanomolar and picomolar Zn(II) binding properties of metallothionein. J Am Chem Soc. 2007;129(35):10911–21. DOI

Kumar S. Occupational and environmental exposure to lead and reproductive health impairment: an overview. Indian J Occup Environ Med. 2018;22(3):128–37.

Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: a review of literature. J Hum Reprod Sci. 2015;8(4):191–6. DOI

Kushawaha B, Yadav RS, Swain DK, Rai PK, Garg SK. Mercury-induced inhibition of tyrosine phosphorylation of sperm proteins and altered functional dynamics of buck spermatozoa: an in vitro study. Biol Trace Elem Res. 2020;198:1–15. DOI

Kushawaha B, Singh-Yadav R, Swain DK, Kumari P, Kumar A, Yadav B, Anand M, Yadav S, Singh D, Garg SK. Collapsed mitochondrial cristae in goat spermatozoa due to mercury result in lethality and compromised motility along with altered kinematic patterns. Sci Rep. 2021;2021(11):646. https://doi.org/10.1038/s41598-020-80235-y . DOI

Lavranos G, Balla M, Tzortzopoulou A, Syriou V, Angelopoulou R. Investigating ROS sources in male infertility: a common end for numerous pathways. Reprod Toxicol. 2012;34:298–307. DOI

Li X, Liu J, Wu S, Zheng W, Li H, Bao S. In utero single low-dose exposure of cadmium induces rat fetal Leydig cell dysfunction. Chemosphere. 2018;194:57–66. https://doi.org/10.1016/j.chemosphere.2017.11.159 . DOI

Liu J, Ren L, Wei J, Zhang J, Zhu Y, Li X, Jing L, Duan J, Zhou X, Sun Z. Fine particle matter disrupts the blood-testis barrier by activating TGF-β3/p38 MAPK pathway and decreasing testosterone secretion in rat. Environ Toxicol. 2018;33(7):711–9. https://doi.org/10.1002/tox.22556 . Epub 2018 Apr 19. DOI

López-Botella A, Velasco I, Acién M, Sáez-Espinosa P, Todolí-Torró JL, Sánchez-Romero R, Gómez-Torres MJ. Impact of heavy metals on human male fertility—an overview. Antioxidants. 2021;10(9):1473. DOI

Løvstad RA. Copper catalyzed oxidation of ascorbate (vitamin C). Inhibitory effect of catalase, superoxide dismutase, serum proteins (ceruloplasmin, albumin, apotransferrin) and amino acids. Int J Biochem. 1987;19(4):309–13. DOI

Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30:42–59. DOI

Lwin TZ, Than AA, Min AZ, Robson MG, Siriwong W. Effects of pesticide exposure on reproductivity of male groundnut farmers in Kyauk Kan village, Nyaung-U, Mandalay region, Myanmar. Risk Manag Healthc Policy. 2018;11:235–41. DOI

Madhu NR, Sarkar B, Biswas SJ, Behera BK, Patra A. Evaluating the anti-fertility potential of α-chlorohydrin on testis and spermatozoa in the adult male wild Indian house rat (Rattus rattus). J Environ Pathol Toxicol Oncol. 2011;30(2):93–102. DOI

Madhu NR, Sarkar B, Patra A, Biswas SJ, Behera BK. Effect of Methylmethane sulphonate and Alpha chlorohydrin on reproductive organs of wild Indian house rat (Rattus rattus). Int J Curr Res Acad Rev. 2014;2(3):24–33.

Mahmoudi R, Azizi A, Abedini S, Hemayatkhah Jahromi V, Abidi H, Jafari Barmak M. Green tea improves rat sperm quality and reduced cadmium chloride damage effect in spermatogenesis cycle. J Med Life. 2018;11:371–80. https://doi.org/10.25122/jml-2018-0005 . DOI

Manisalidis I, Stavropoulou E, Stavropoulos A, Bezirtzoglou E. Environmental and health impacts of air pollution: a review. Front Public Health. 2020;8:14. 13 pages. DOI

Marcho C, Oluwayiose OA, Pilsner JR. The preconception environment and sperm epigenetics. Andrology. 2020;2020(8):924–42. DOI

Maresch CC, Stute DC, Alves MG, Oliveira PF, de Kretser DM, Linn T. Diabetes-induced hyperglycemia impairs male reproductive function: a systematic review. Hum Reprod Update. 2018;24(1):86–105. DOI

Marshall G, Ferreccio C, Yuan Y, Bates MN, Steinmaus C, Selvin S. Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst. 2007;99:920–8. DOI

Martinez CS, Escobar AG, Torres JGD, Brum DS, Santos FW, Alonso MJ, … Wiggers GA. Chronic exposure to low doses of mercury impairs sperm quality and induces oxidative stress in rats. J Toxicol Environ Health A. 2014;77(1–3):143–154.

Martinez CS, Peçanha FM, Brum DS, Santos FW, Franco JL, Zemolin APP, Anselmo-Franci JA, Fernando BJ, Alonso MJ, Salaices M, Vassallo DV, Leivas FG, Wiggers GA. Reproductive dysfunction after mercury exposure at low levels: evidence for a role of glutathione peroxidase (GPx) 1 and GPx4 in male rats. Reprod Fertil Dev. 2020;29(9):1803–12. https://doi.org/10.1071/RD16310 . DOI

Massányi P, Massányi M, Madeddu R, Stawarz R, Lukáˇc N. Effects of cadmium, lead, and mercury on the structure and function of reproductive organs. Toxics. 2020;2020(8):94. https://doi.org/10.3390/toxics8040094 . DOI

Mattison DR, Plowchalk DR, Meadows M. Reproductive toxicity: male and female reproductive systems as targets for chemical injury. Med Clin North Am. 1990;74:391411. DOI

McMaster SB. Developmental toxicity, reproductive toxicity, and neurotoxicity as regulatory endpoints. Toxicol Lett. 1993;68:225–30. DOI

Menezo Y, Dale B, Elder K. Link between increased prevalence of autism spectrum disorder syndromes and oxidative stress, DNA methylation and imprinting: the effect of the environment. JAMA Pediatr. 2015;169:1066–7. DOI

Menezo Y, Patrice P, Clement C, Clement A, Elder K. Methylation: an ineluctable biochemical and physiological process essential to the transmission of life. Int J Mol Sci. 2020;21(23):9311. DOI

Merino G, Lira SC, Martínez-Chéquer JC. Effects of cigarette smoking on semen characteristics of a population in Mexico. Arch Androl. 1998;41:11–5. DOI

Michelakis ED, Hampl V, Nsair A. Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res. 2002;90:1307–15. DOI

Mojiri A, Zhou JL, Ohashi A, Ozaki N, Kindaichi T. Comprehensive review of polycyclic aromatic hydrocarbons in water sources, their effects and treatments. Sci Total Environ. 2019;2019:133971. https://doi.org/10.1016/j.scitotenv.2019.133971 . DOI

Monick MM, Beach SRH, Plume J. Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers. Am J Med Genet B Neuropsychiatr Genet. 2012;159(2):141–51. DOI

Morielli T, O’Flaherty C. Oxidative stress impairs function and increases redox protein modifications in human spermatozoa. Reproduction. 2015;149:113–23. https://doi.org/10.1530/REP-14-0240 . DOI

Morris MC, Evans DA, Tangney CC, Bienias JL, Schneider JA, Wilson RS. Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Arch Neurol. 2006;63:1085–8. DOI

Mukhopadhyay D, Mitra A, Nandi P, Varghese AC, Murmu N, Chowdhury R. Expression of metallothionein-1 (MT-1) mRNA in the rat testes and liver after cadmium injection. Syst Biol Reprod Med. 2009;55:188–92. DOI

Münzel T, Sørensen M, Schmidt F, Schmidt E, Steven S, Kröller-Schön S, Daiber A. The adverse effects of environmental noise exposure on oxidative stress and cardiovascular risk. Antioxid Redox Signal. 2018;28(9):873–908. DOI

Nemmar A, Hoet PHM, Vanquickenborne B. Passage of inhaled particles into the blood circulation in humans. Circulation. 2002;105:411–4. DOI

Nickens KP, Patierno SR, Ceryak S. Chromium genotoxicity: a double-edged sword. Chem Biol Interact. 2010;188:276–88. DOI

Niedzwiecki MM, Hall MN, Liu X. A dose-response study of arsenic exposure and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults. Environ Health Perspect. 2013;121(11–12):1306–12. DOI

Nurmatov UB, Tagiyeva N, Semple S, Devereux G, Sheikh A. Volatile organic compounds and risk of asthma and allergy: a systematic review. Eur Respir Rev. 2015;24:92–101. DOI

O’Donnell L, Stanton P, de Kretser DM. Endocrinology of the male reproductive system and spermatogenesis. In: Endotext [Internet]. MDText.com , Inc.; 2017. p. 1–62.

Omolaoye TS, Shahawy OE, Skosana BT, Boillat T, Loney T, du Plessis SS. The mutagenic science and pollution research effect of tobacco smoke on male fertility. Environ Sci Pollut Res. 2021;2021. https://doi.org/10.1007/s11356-021-16331-x .

Orlando C, Caldini AL, Barni T, Wood WG, Strasburger CJ, Natali A. Ceruloplasmin and transferrin in human seminal plasma: are they an index of seminiferous tubular function? Fertil Steril. 1985;43:290–4. DOI

Pagano G. Redox-modulated xenobiotic action and ROS formation: a mirror or a window? Hum Exp Toxicol. 2002;21:77–81. DOI

Parran DK, Barone S Jr, Mundy WR. Methylmercury decreases NGF-induced TrkA autophosphorylation and neurite outgrowth in PC12 cells. Brain Res Dev Brain Res. 2003;141:71–81. DOI

Pereira SC, Oliveira PF, Oliveira SR, Pereira MDL, Alves MG. Impact of environmental and lifestyle use of chromium on male fertility: focus on antioxidant activity and oxidative stress. Antioxidants. 2021;2021(10):1365. https://doi.org/10.3390/antiox10091365 . DOI

Pilsner JR, Shershebnev A, Medvedeva YA. Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults. Reprod Toxicol. 2018;78:40–9. DOI

Pizent A, Tariba B, Živković T. Reproductive toxicity of metals in men. Arh Hig Rada Toksikol. 2012;63(Suppl 1):35–46.

Pope CA, Burnett RT, Thurston GD. Cardiovascular mortality and long-term exposure to particulate air pollution. Circulation. 2004;109:71. DOI

Priyanka M, Ketki D, Hyacinth H. Cytotoxic effects of benzene metabolites on human sperm function: an in vitro study. ISRN Toxicol. 2013;2013:397524.

Pryor WA. Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity. Environ Health Perspect. 1997;105(suppl 4):875–82. DOI

Rădulescu A, Lundgren S. A pharmacokinetic model of lead absorption and calcium competitive dynamics. Sci Rep. 2019;9:14225. DOI

Ray PD, Yosim A, Fry RC. Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges. Front Genet. 2014;5(article 201):1–26.

Rehman R, Zahid N, Amjad S, Baig M, Gazzaz ZJ. Relationship between smoking habit and sperm parameters among patients attending an infertility clinic. Front Physiol. 2019;2019(10):1356. https://doi.org/10.3389/fphys.2019.01356 . DOI

Ren XY, Zhou Y, Zhang JP, Feng WH, Jiao BH. Expression of metallothionein gene at different time in testicular interstitial cells and liver of rats treated with cadmium. World J Gastroenterol. 2003;9:1554–8. DOI

Ren T, Chen X, Ge Y, Zhao L, Zhong R. Determination of heavy metals in cigarettes using high-resolution continuum source graphite furnace atomic absorption spectrometry. Anal Methods. 2017;9:4033–43. DOI

Rizvi A, Parveen S, Khan S, Naseem I. Nickel toxicology with reference to male molecular reproductive physiology. Reprod Biol. 2020;20(2020):3–8. DOI

Ronco AM, Arguello G, Muñoz L, Gras N, Llanos M. Metals content in placentas from moderate cigarette consumers: correlation with newborn birth weight. Biometals. 2005;18(3):233–241.

Rooney KL, Domar AD. The relationship between stress and infertility. Dialogues Clin Neurosci. 2018;20(1):41–7. DOI

Roychoudhury S, Chakraborty S, Choudhury AP, Das A, Jha NK, Slama P, Nath M, Massanyi P, Ruokolainen J, Kesari KK. Environmental factors-induced oxidative stress: hormonal and molecular pathway disruptions in hypogonadism and erectile dysfunction. Antioxidants. 2021;10:837. DOI

Saleh RA, Agarwal A. Oxidative stress and male infertility: from research bench to clinical practice. J Androl. 2002;23:737–52.

Saleh RA, Agarwal A, Sharma RK, Nelson DR, Thomas AJ Jr. Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: a prospective study. Fertil Steril. 2002;78:491–9. DOI

Salnikow K, Zhitkovich A. Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic and chromium. Chem Res Toxicol. 2008;21:28–44. DOI

Sarkar M, Chaudhuri GR, Chattopadhyay A, Biswas NM. Effect of sodium arsenite on spermatogenesis, plasma gonadotrophins and testosterone in rats. Asian J Androl. 2003;5:27–31.

Sedha S, Kumar S, Shukla S. Role of oxidative stress in male reproductive dysfunctions with reference to phthalate compounds. Urol J. 2015;12(5):2304–16.

Seow WJ, Kile ML, Baccarelli AA. Epigenome wide DNA methylation changes with development of arsenic induced skin lesions in Bangladesh: a case-control follow-up study. Environ Mol Mutagen. 2014;55(6):449–56. DOI

Shankar S, Shanker U, Shikha. Arsenic contamination of groundwater: a review of sources, prevalence, health risks, and strategies for mitigation. ScientificWorldJournal. 2014;2014:304524. 18 pages DOI

Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, Rajkovic J, Fokou PVT, Azzini E, Peluso I, Mishra AP, Nigam M, El Rayess Y, El Beyrouthy M, Polito L, Iriti M, Martins N, Martorell M, Docea AO, Setzer WN, Calina D, Cho WC, Sharifi-Rad J. Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Front Physiol. 2020;11:694. https://doi.org/10.3389/fphys.2020.00694 . DOI

Sharma A, Bhagat M, Mohammad Urfan M, Ahmed B, Anima Langer A, Villayat Ali V, Vyas D, Yadav NS, Hakla HR, Sharma S, Pal S. Nickel excess affects phenology and reproductive attributes of Asterella wallichiana and Plagiochasma appendiculatum growing in natural habitats. Nat Portf. 2021;11:1169.

Shaw CA, Robertson S, Miller MR. Diesel exhaust particulate – exposed macrophages cause marked endothelial cell activation. Am J Respir Cell Mol Biol. 2011;44(6):840–51. DOI

Shen Y, Shen HM, Shi CY, Ong CN. Benzene metabolites enhance reactive oxygen species generation in HL60 human leukemia cells. Hum Exp Toxicol. 1996;15:422–7. DOI

Sone H, Akanuma H, Fukuda T. Oxygenomics in environmental stress. Redox Rep. 2010;15(3):98–114. DOI

Stanwell-Smith R, Thompson SG, Haines AP, Ward RJ, Cashmore G, Stedronska J, Hendry WF. A comparative study of zinc, copper, cadmium, and lead levels in fertile and infertile men. Fertil Steril. 1983;40:670–7. DOI

Steeno OP, Pangkahila A. Occupational influences on male fertility and sexuality. Andrologia. 1984;16:93–101. DOI

Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med. 1995;18:321–36. DOI

Sugihara T, Wadhwa R, Kaul SC, Mitsui Y. A novel testis-specific metallothionein-like protein, tesmin, is an early marker of male germ cell differentiation. Genomics. 1999;57:130–6. DOI

Suman S, Sinha A, Tarafdar A. Polycyclic aromatic hydrocarbons (PAHs) concentration levels, pattern, source identification and soil toxicity assessment in urban traffic soil of Dhanbad, India. Sci Total Environ. 2016;545:353–60. https://doi.org/10.1016/j.scitotenv.2015.12.061 . DOI

Sun YY, Yu HX, Zhang JF, Yin Y, Shi HH, Wang XR. Bioaccumulation, depuration and oxidative stress in fish Carassius auratus under phenanthrene exposure. Chemosphere. 2006;63:1319–27. DOI

Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP. Effects of cadmium on DNA-(Cytosine-5) methyl transferase activity and DNA methylation status during cadmium- induced cellular transformation. Exp Cell Res. 2003;286:355–65. DOI

Taverne YJHJ, Bogers AJJC, Duncker DJ, Merkus D. Reactive oxygen species and the cardiovascular system. Oxid Med Cell Longev. 2013;862423:1–15.

Telisman S, Colak B, Pizent A, Jurasović J, Cvitković P. Reproductive toxicity of low-level lead exposure in men. Environ Res. 2007;105:256–66. DOI

Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E. Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. Environ Health Perspect. 2012;120:1017–22. DOI

Tian H, Chen S, Leng Y, Li T, Li Z, Chen H. Exposure to cadmium during gestation and lactation affects development and function of Leydig cells in male offspring. Environ Toxicol. 2018;33:351–60. https://doi.org/10.1002/tox.22522 . DOI

Tian M, Liu L, Zhang J, Huang Q, Shen H. Positive association of low-level environmental phthalate exposure with sperm motility was mediated by DNA methylation: a pilot study. Chemosphere. 2019;220:459–67. DOI

Tiwari S, Tripathi I, Tiwari H. Effects of lead on environment. Int J Emerg Res Manag Technol. 2013;2(6):1–5.

Tomoum HY, Mostafa GA, Ismail NA, Ahmed SM. Lead exposure and its association with pubertal development in school-age Egyptian children: pilot study. Pediatr Int. 2010;52:89–93. DOI

Trang NT, Huyen VT. Polymorphism of xenobiotic detoxification genes and male infertility. Male reproductive health. Intech Open, London. 2018:1–19.

Tremellen K. Oxidative stress and male infertility – a clinical perspective. Hum Reprod Update. 2008;14:243–58. DOI

Tvrda E, Peer R, Sikka RC, Agarwal A. Iron and copper in male reproduction: a double-edged sword. J Assist Reprod Genet. 2015;32(1):3–16. DOI

Vachhrajani KD, Chowdhury AR. Distribution of mercury and evaluation of testicular steroidogenesis in mercuric chloride and methylmercury administered rats. Indian J Exp Biol. 1990;28:746–51.

Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem. 2005;12:1161–208. DOI

Varga B, Zsolnai B, Paksy K, Naray M, Ungvary G. Age dependent accumulation of cadmium in the human ovary. Reprod Toxicol. 1993;7:225–8. DOI

Vested A, Giwercman A, Bonde JP, Gunnar T. Persistent organic pollutants and male reproductive health. Asian J Androl. 2014;16:71–80. DOI

Williams PL, Sergeyev O, Lee MM, Korrick SA, Burns JS, Humblet O. Blood lead levels and delayed onset of puberty in a longitudinal study of Russian boys. Pediatrics. 2010;125:e1088–96. DOI

Wirth JJ, Mijal RS. Adverse effects of low level heavy metal exposure on male reproductive function. Syst Biol Reprod Med. 2010;56:147–67. DOI

Wu H, Estill MS, Shershebnev A. Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study. Hum Reprod. 2017;32:2159–69. DOI

Xiao X, Mruk DD, Tang EI, Wong CK, Lee WM, John CM. Environmental toxicants perturb human Sertoli cell adhesive function via changes in F-actin organization mediated by actin regulatory proteins. Hum Reprod. 2014;29:1279–91. https://doi.org/10.1093/humrep/deu011 . DOI

Xi-Ning C, Chao Y, Dong Y, Liu JP, Ckeng JJ, Zhou Y, Long CL, He DW, Lin T, Shen LJ, Guang-Hui W. Fine particulate matter leads to reproductive impairment in male rats by overexpressing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Toxicol Lett. 2015;237(3):181–90. DOI

Yang TY, Hsu LI, Chiu AW. Comparison of genome wide DNA methylation in urothelial carcinomas of patients with and without arsenic exposure. Environ Res. 2014;128:57–63. DOI

Yilmaz B, Kutlu S, Canpolat S, Sandal S, Ayar A, Mogulcok R, Kelestimar H. Effects of paint thinner exposure on serum LH, FSH and testosterone: levels and hypothalamic catecholamine. Biol Pharm Bull. 2001;24(2):163–6. DOI

Yuan Y, Marshall G, Ferreccio C, Steinmaus C, Selvin S, Liaw J. Acute myocardial infarction mortality in comparison with lung and bladder cancer mortality in arsenic-exposed region II of Chile from 1950 to 2000. Am J Epidemiol. 2007;166:1381–91. DOI

Zavitsanos K, Nunes AM, Malandrinos G, Hadjiliadis N. Copper effective binding with 32–62 and 94–125 peptide fragments of histone H2B. J Inorg Biochem. 2011;105:102–10. DOI

Zhang Y, Yang R, Burwinkel B. F2RL3 methylation in blood DNA is a strong predictor of mortality. Int J Epidemiol. 2014;43(4):1215–25. DOI

Zhang J, Huang B, Hu G, Zhan X, Xie T, Li S. Aldosterone blocks rat stem Leydig cell development in vitro. Front Endocrinol. 2018;9:4. DOI

Zhang Y, Wang B, Cheng Q, Li X, Li Z. Removal of toxic heavy metal ions (Pb, Cr, Cu, Ni, Zn, Co, Hg, and Cd) from waste batteries or lithium cells using nanosized metal oxides: a review. J Nanosci Nanotechnol. 2020;2020(20):7231–54. DOI

Zhao LL, Ru YF, Liu M, Tang JN, Zheng JF, Wu B. Reproductive effects of cadmium on sperm function and early embryonic development in vitro. PLoS One. 2017;12:e0186727. https://doi.org/10.1371/journal.pone.0186727 . DOI

Zheng H, Zhou X, Li DK. Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017;12:e0178535. DOI

Zhitkovich A. Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI). Chem Res Toxicol. 2005;18:3–11. DOI

Zhou L, Su X, Li B, Chu C, Sun H, Zhang N, Han B, Li C, Zou B, Niu Y, Zhang R. PM DOI

Zhu J, Wang H, Yang S, Guo L, Li Z, Wang W, Wang S, Huang W, Wang L, Yang T, Ma Q, Bi Y. Comparison of toxicity of benzene metabolite hydroquinone in hematopoietic stem cells derived from murine embryonic yolk sac and adult bone marrow. PLoS One. 2013;5(8):e71153. DOI

Zhu Q, Ge F, Dong Y, Sun W, Wang Z, Shan Y. Comparison of flavonoids and isoflavonoids to inhibit rat and human 11β-hydroxysteroid dehydrogenase 1 and 2. Steroids. 2018;132:25–32. DOI

Zhu Q, Li X, Ge RS. Toxicological effects of cadmium on mammalian testis. Front Genet. 2020;2020(11):527. DOI