Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Zinc and selenium attenuate quaternary heavy metal mixture-induced testicular damage via amplification of the antioxidant system, reduction in metal accumulation, inflammatory and apoptotic biomarkers

  • Harrison Ozoani (African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt) ;
  • Anthonet N. Ezejiofor (African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt) ;
  • Kenneth O. Okolo (Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Science and Technology) ;
  • Chinna N. Orish (Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt) ;
  • Ana Cirovic (Faculty of Medicine, Institute of Anatomy, University of Belgrade) ;
  • Aleksandar Cirovic (Faculty of Medicine, Institute of Anatomy, University of Belgrade) ;
  • Orish E. Orisakwe (African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt)
  • Received : 2023.01.09
  • Accepted : 2023.04.26
  • Published : 2023.07.15
⟨ Previous Next ⟩

Abstract

Heavy metals (HMs) such as cadmium (Cd), lead (Pb), arsenic (As), and mercury (Hg) are highly toxic elements. They are often found together in nature as a heavy metal mixture (HMM) and are known to contribute to subfertility/infertility as environmental pollutants. This study aims to evaluate the potential benefits of treating HMM-induced testicular pathophysiology with zinc (Zn) and/or selenium (Se). Six-week-old male Sprague Dawley rats were grouped into 5 (n=7). The control group received deionized water, while the other groups were treated with PbCl2 (20 mg kg-1), CdCl2 (1.61 mg kg-1), HgCl2 (0.40 mg kg-1), and Na2AsO3 (10 mg kg-1) in deionized water for 60 days. Additionally, groups III to V received Zn, Se, and Zn/Se, respectively, for 60 days. The study evaluated testis weight, metal accumulation, sperm analysis, FSH, LH, testosterone, prolactin, oxidative stress, antioxidants, pro-inflammatory and apoptotic markers, and presented structural changes in the testis as micrographs. HMM caused a significant increase in testis weight, metal accumulation, prolactin, oxidative stress, and pro-inflammatory and apoptotic markers, while significantly decreasing semen analysis, FSH, LH, and testosterone. Histology showed decreased spermatogenesis and spermiogenesis, as evidenced by the structure of the germ cells and spermatids. However, Zn, Se, or both ameliorated and reversed some of the observed damages. This study provides further evidence for the mitigative potential of Zn, Se, or both in reversing the damage inflicted by HMM in the testis, and as a countermeasure towards improving HM-induced decrease in public health fecundity.

Keywords

References

  1. Kocadal K, Alkas FB, Battal D, Saygi S (2020) Cellular pathologies and genotoxic effects arising secondary to heavy metal exposure: a review. Hum Exp Toxicol 39:3-13. https://doi.org/10.1177/0960327119874439
  2. Fu Z, Xi S (2020) The effects of heavy metals on human metabolism. Toxicol Mech Methods 30:167-176. https://doi.org/10.1080/15376516.2019.1701594
  3. Pujari M, Kapoor D (2021) Heavy metals in the ecosystem: sources and their effects. In: Heavy metals in the environment. Elsevier, pp 1-7
  4. Kim D-W, Ock J, Moon K-W, Park C-H (2021) Association between Pb, Cd, and Hg exposure and liver injury among Korean adults. Int J Environ Res Public Health 18:6783. https://doi.org/10.3390/ijerph18136783
  5. Chalabis-Mazurek A, Valverde Piedra JL, Muszynski S et al (2021) The concentration of selected heavy metals in muscles, liver and kidneys of pigs fed standard diets and diets containing 60% of new rye varieties. Animals (Basel) 11:1377. https://doi.org/10.3390/ani11051377
  6. Ezedom T, Asagba SO (2016) Effect of a controlled food-chain mediated exposure to cadmium and arsenic on oxidative enzymes in the tissues of rats. Toxicol Rep 3:708-715. https://doi.org/10.1016/j.toxrep.2016.07.002
  7. Orr SE, Barnes MC, George HS et al (2018) Exposure to mixtures of mercury, cadmium, lead, and arsenic alters the disposition of single metals in tissues of Wistar rats. J Toxicol Environ Health Part A 81:1246-1256. https://doi.org/10.1080/15287394.2018.1551164
  8. FAO/WHO J (2014) Safety evaluation of certain food additives and contaminants, vol 68. World Health Organization
  9. Binns HJ, Campbell C, Brown MJ; Advisory Committee on Childhood Lead Poisoning Prevention (2007) Interpreting and managing blood lead levels of less than 10 ㎍/dL in children and reducing childhood exposure to lead: recommendations of the centers for disease control and prevention advisory committee on childhood lead poisoning prevention. Pediatrics 120(5): e1285-98 https://doi.org/10.1542/peds.2005-1770
  10. Wang X, Wang M, Dong W et al (2013) Subchronic exposure to lead acetate inhibits spermatogenesis and downregulates the expression of Ddx3y in testis of mice. Reprod Toxicol (Elmsford, NY) 42:242-250. https://doi.org/10.1016/j.reprotox.2013.10.003
  11. Adhikari N, Sinha N, Narayan R, Saxena D (2001) Lead-induced cell death in testes of young rats. J Appl Toxicol 21:275-277. https://doi.org/10.1002/jat.754
  12. Mann U, Shif B, Patel P (2020) Reasons for worldwide decline in male fertility. Curr Opin Urol 30:296-301. https://doi.org/10.1097/MOU.0000000000000745
  13. Levine H, Jorgensen N, Martino-Andrade A et al (2017) Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 23:646-659. https://doi.org/10.1093/humupd/dmx022
  14. Agarwal A, Mulgund A, Hamada A, Chyatte MR (2015) A unique view on male infertility around the globe. Reprod Biol Endocrinol 13:37. https://doi.org/10.1186/s12958-015-0032-1
  15. Dalton TP, He L, Wang B et al (2005) Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc Natl Acad Sci 102:3401-3406. https://doi.org/10.1073/pnas.0406085102
  16. Cheng CY, Mruk DD (2012) The blood-testis barrier and its implications for male contraception. Pharmacol Rev 64:16-64. https://doi.org/10.1124/pr.110.002790
  17. da Silva RF, Borges CDS, de Almeida LC, Cagnon VHA, de Grava KW (2017) Arsenic trioxide exposure impairs testicular morphology in adult male mice and consequent fetus viability. J Toxicol Environ Health Part A 80:1166-1179. https://doi.org/10.1080/15287394.2017.1376405
  18. Cupertino MC, Novaes RD, Santos EC et al (2017) Differential susceptibility of germ and leydig cells to cadmium-mediated toxicity: impact on testis structure, adiponectin levels, and steroidogenesis. Oxid Med Cell Longev 2017:3405089. https://doi.org/10.1155/2017/3405089
  19. Zhu Q, Li X, Ge RS (2020) Toxicological effects of cadmium on mammalian testis. Front Genet 11:527. https://doi.org/10.3389/fgene.2020.00527
  20. Nna VU, Ujah GA, Mohamed M et al (2017) Cadmium chloride-induced testicular toxicity in male wistar rats; prophylactic effect of quercetin, and assessment of testicular recovery following cadmium chloride withdrawal. Biomed Pharmacother 94:109-123. https://doi.org/10.1016/j.biopha.2017.07.087
  21. Grande G, Barrachina F, Soler-Ventura A et al (2022) The role of testosterone in spermatogenesis: lessons from proteome profiling of human spermatozoa in testosterone deficiency. Front Endocrinol (Lausanne) 13:852661. https://doi.org/10.3389/fendo.2022.852661
  22. Iavicoli I, Fontana L, Bergamaschi A (2009) The effects of metals as endocrine disruptors. J Toxicol Environ Health Part B Crit Rev 12:206-223. https://doi.org/10.1080/10937400902902062
  23. Tamas MJ, Sharma SK, Ibstedt S, Jacobson T, Christen P (2014) Heavy metals and metalloids as a cause for protein misfolding and aggregation. Biomolecules 4:252-267. https://doi.org/10.3390/biom4010252
  24. Yilmaz B, Terekeci H, Sandal S, Kelestimur F (2020) Endocrine disrupting chemicals: exposure, effects on human health, mechanism of action, models for testing and strategies for prevention. Rev Endocr Metab Disord 21:127-147. https://doi.org/10.1007/s11154-019-09521-z
  25. Casals-Casas C, Desvergne B (2011) Endocrine disruptors: from endocrine to metabolic disruption. Annu Rev Physiol 73:135-162. https://doi.org/10.1146/annurev-physiol-012110-142200
  26. Lafuente A, Marquez N, Perez-Lorenzo M, Pazo D, Esquifino AI (2001) Cadmium effects on hypothalamic-pituitary-testicular axis in male rats. Exp Biol Med 226:605-611. https://doi.org/10.1177/153537020122600615
  27. Yi L, Shang X-J, Lv L et al (2022) Cadmium-induced apoptosis of Leydig cells is mediated by excessive mitochondrial fission and inhibition of mitophagy. Cell Death Dis 13:1-13. https://doi.org/10.1038/s41419-022-05364-w
  28. Kasperczyk A, Dobrakowski M, Czuba ZP, Horak S, Kasperczyk S (2015) Environmental exposure to lead induces oxidative stress and modulates the function of the antioxidant defense system and the immune system in the semen of males with normal semen profle. Toxicol Appl Pharmacol 284:339-344. https://doi.org/10.1016/j.taap.2015.03.001
  29. Wang Y, Wang K, Han T et al (2020) Exposure to multiple metals and prevalence for preeclampsia in Taiyuan, China. Environ Int 145:106098. https://doi.org/10.1016/j.envint.2020.106098
  30. Porru S, Alessio L (1996) The use of chelating agents in occupational lead poisoning. Occup Med (Oxford, England) 46:41-48. https://doi.org/10.1093/occmed/46.1.41
  31. Olechnowicz J, Tinkov A, Skalny A, Suliburska J (2018) Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci 68:19-31. https://doi.org/10.1007/s12576-017-0571-7
  32. Ge J, Liu LL, Cui ZG et al (2021) Comparative study on protective effect of different selenium sources against cadmium-induced nephrotoxicity via regulating the transcriptions of selenoproteome. Ecotoxicol Environ Saf 215:112135. https://doi.org/10.1016/j.ecoenv.2021.112135
  33. Skalny AA, Tinkov AA, Medvedeva YS et al (2015) Effect of short-term zinc supplementation on zinc and selenium tissue distribution and serum antioxidant enzymes. Acta scientiarum polonorum Technologia alimentaria 14:269-276. https://doi.org/10.17306/J.AFS.2015.3.28
  34. Zhang D, Liu J, Gao J et al (2014) Zinc supplementation protects against cadmium accumulation and cytotoxicity in Madin-Darby bovine kidney cells. PLoS One 9:e103427. https://doi.org/10.1371/journal.pone.0103427
  35. Onakpa MM, Njan AA, Kalu OC (2018) A review of heavy metal contamination of food crops in Nigeria. Ann Glob Health 84:488-494. https://doi.org/10.29024/aogh.2314
  36. Vodela JK, Renden JA, Lenz SD, McElhenney WH, Kemppainen BW (1997) Drinking water contaminants (arsenic, cadmium, lead, benzene, and trichloroethylene). 1. Interaction of contaminants with nutritional status on general performance and immune function in broiler chickens. Poult Sci 76:1474-1492. https://doi.org/10.1093/ps/76.11.1474
  37. Anyanwu BO, Orish CN, Ezejiofor AN, Nwaogazie IL, Orisakwe OE (2020) Protective effect of costus afer aqueous leaf extract (CALE) on low-dose heavy metal mixture-induced alterations in serum lipid profile and hematological parameters of male wistar albino rats. J Toxicol 2020:8850264. https://doi.org/10.1155/2020/8850264
  38. Anyanwu BO, Orish CN, Ezejiofor AN, Nwaogazie IL, Orisakwe OE (2020) Neuroprotective effect of Costus afer on low dose heavy metal mixture (lead, cadmium and mercury) induced neurotoxicity via antioxidant, anti-inflammatory activities. Toxicol Rep 7:1032-1038. https://doi.org/10.1016/j.toxrep.2020.08.008
  39. Institoris L, Kovacs D, Kecskemeti-Kovacs I, Lukacs A, Szabo A, Lengyel Z, Papp A, Nagymajtenyi L, Desi I (2006) Immuno-toxicological investigation of subacute combined exposure with low doses of Pb, Hg and Cd in rats. Acta Biol Hung 57:433-439. https://doi.org/10.1556/ABiol.57.2006.4.5
  40. Eddie-Amadi BF, Ezejiofor AN, Orish CN, Orisakwe OE (2022) Zinc and selenium mitigated heavy metals mixture (Pb, Al, Hg and Mn) mediated hepatic-nephropathy via modulation of oxido-inflammatory status and NF-kB signaling in female albino rats. Toxicology 481:153350. https://doi.org/10.1016/j.tox.2022.153350
  41. Liu G, Xie C, Fang Y et al (2018) Splenectomy after partial hepatectomy accelerates liver regeneration in mice by promoting tight junction formation via polarity protein Par 3-aPKC. Life Sci 192:91-98. https://doi.org/10.1016/j.lfs.2017.11.032
  42. Kumar A, Nagar M (2014) Histomorphometric study of testis in deltamethrin treated albino rats. Toxicol Rep 1:401-410. https://doi.org/10.1016/j.toxrep.2014.07.005
  43. Okoye EA, Bocca B, Ruggieri F, Ezejiofor AN, Nwaogazie IL, Domingo JL, Rovira J, Frazzoli C, Orisakwe OE (2021) Metal pollution of soil, plants, feed and food in the Niger Delta, Nigeria: health risk assessment through meat and fish consumption. Environ Res 198:111273. https://doi.org/10.1016/j.envres.2021.111273
  44. Slott VL, Suarez JD, Perreault SD (1991) Rat sperm motility analysis: methodologic considerations. Reprod Toxicol (Elmsford, NY) 5:449-458. https://doi.org/10.1016/0890-6238(91)90009-5
  45. Chapin RE, Filler RS, Gulati D et al (1992) Methods for assessing rat sperm motility. Reprod Toxicol (Elmsford, NY) 6:267-273. https://doi.org/10.1016/0890-6238(92)90183-t
  46. Moskovtsev SI, Librach CL (2013) Methods of sperm vitality assessment. Methods Mol Biol (Clifton, NJ) 927:13-19. https://doi.org/10.1007/978-1-62703-038-0_2
  47. Gupta A, Kumar A, Naqvi S, Flora SJS (2021) Chronic exposure to multi-metals on testicular toxicity in rats. Toxicol Mech Methods 31:53-66. https://doi.org/10.1080/15376516.2020.1828522
  48. Maremanda KP, Khan S, Jena G (2014) Zinc protects cyclophosphamide-induced testicular damage in rat: involvement of metallothionein, tesmin and Nrf2. Biochem Biophys Res Commun 445:591-596. https://doi.org/10.1016/j.bbrc.2014.02.055
  49. Haugen TB, Grotmol T (1998) pH of human semen. Int J Androl 21:105-108. https://doi.org/10.1046/j.1365-2605.1998.00108.x
  50. Lin MC, Tsai TC, Yang YS (1992) Measurement of viscosity of human semen with a rotational viscometer. J Formos Med Assoc 91:419-423
  51. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351-358. https://doi.org/10.1016/0003-2697(79)90738-3
  52. Sosroseno W, Sugiatno E, Samsudin AR, Ibrahim MF (2008) The role of nitric oxide on the proliferation of a human osteoblast cell line stimulated with hydroxyapatite. J Oral Implantol 34:196-202. https://doi.org/10.1563/0.910.1
  53. Oktem G, Uysal A, Oral O et al (2012) Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Exp Toxicol Pathol 64:471-479. https://doi.org/10.1016/j.etp.2010.11.001
  54. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science 179:588-590. https://doi.org/10.1126/science.179.4073.588
  55. Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 25:192-205. https://doi.org/10.1016/0003-2697(68)90092-4
  56. Jollow D, Mitchell J, Zampaglione N, Gillette J (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151-169. https://doi.org/10.1159/000136485
  57. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170-3175 https://doi.org/10.1016/S0021-9258(19)45228-9
  58. Bergmeyer H, Berat E, Schmid F, Stark H (1974) Methods of enzymatic analysis, 2nd edn. Verlag Chemie, Weinheim and Academic Press, New York and London
  59. Siu ER, Mruk DD, Porto CS, Cheng CY (2009) Cadmium-induced testicular injury. Toxicol Appl Pharmacol 238:240-249. https://doi.org/10.1016/j.taap.2009.01.028
  60. Aoyagi T, Ishikawa H, Miyaji K, Hayakawa K, Hata M (2002) Cadmium-induced testicular damage in a rat model of subchronic intoxication. Reprod Med Biol 1:59-63. https://doi.org/10.1046/j.1445-5781.2002.00010.x
  61. Yu HT, Zhen J, Leng JY, Cai L, Ji HL, Keller BB (2021) Zinc as a countermeasure for cadmium toxicity. Acta Pharmacol Sin 42:340-346. https://doi.org/10.1038/s41401-020-0396-4
  62. Batra N, Nehru B, Bansal M (2001) Influence of lead and zinc on rat male reproduction at 'biochemical and histopathological levels.' J Appl Toxicol 21:507-512. https://doi.org/10.1002/jat.796
  63. Rafque M, Khan N, Perveen K, Naqvi A (2009) The effects of lead and zinc on the quality of semen of albino rats. J Coll Physicians Surg Pak 19:510-513
  64. Liu L, Yang B, Cheng Y, Lin H (2015) Ameliorative effects of selenium on cadmium-induced oxidative stress and endoplasmic reticulum stress in the chicken kidney. Biol Trace Elem Res 167:308-319. https://doi.org/10.1007/s12011-015-0314-7
  65. Rahman MM, Hossain KFB, Banik S et al (2019) Selenium and zinc protections against metal-(loids)-induced toxicity and disease manifestations: a review. Ecotoxicol Environ Saf 168:146-163. https://doi.org/10.1016/j.ecoenv.2018.10.054
  66. Amara S, Abdelmelek H, Garrel C et al (2008) Preventive effect of zinc against cadmium-induced oxidative stress in the rat testis. J Reprod Dev 54:129-134. https://doi.org/10.1262/jrd.18110
  67. Souza ACF, Marchesi SC, Domingues de Almeida Lima G et al (2016) Effects of sodium arsenite and arsenate in testicular histomorphometry and antioxidants enzymes activities in rats. Biol Trace Elem Res 171:354-362. https://doi.org/10.1007/s12011-015-0523-0
  68. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ (2012) Heavy metal toxicity and the environment. Experientia Suppl 2012:133-164. https://doi.org/10.1007/978-3-7643-8340-4_6
  69. Shimada H, Narumi R, Nagano M, Yasutake A, Waalkes MP, Imamura Y (2009) Strain difference of cadmium-induced testicular toxicity in inbred Wistar-Imamichi and Fischer 344 rats. Arch Toxicol 83:647-652. https://doi.org/10.1007/s00204-009-0442-y
  70. David M, Jahan S, Hussain J et al (2022) Biochemical and reproductive biomarker analysis to study the consequences of heavy metal burden on health profile of male brick kiln workers. Sci Rep 12:7172. https://doi.org/10.1038/s41598-022-11304-7
  71. Bashandy SAE-M, Omara EAA, Ebaid H, Amin MM, Soliman MS (2016) Role of zinc as an antioxidant and anti-inflammatory to relieve cadmium oxidative stress induced testicular damage in rats. Asian Pac J Trop Biomed 6:1056-1064. https://doi.org/10.1016/j.apjtb.2016.08.016
  72. Chen X-W, Chu J-H, Li L-X, Gao P-C, Wang Z-Y, Fan R-F (2022) Protective mechanism of selenium on mercuric chloride-induced testis injury in chicken via p38 MAPK/ATF2/iNOS signaling pathway. Theriogenology 187:188-194. https://doi.org/10.1016/j.theriogenology.2022.05.007
  73. Balali-Mood M, Naseri K, Tahergorabi Z, Khazdair MR, Sadeghi M (2021) Toxic mechanisms of five heavy metals: Mercury, Lead, Chromium, Cadmium, and Arsenic. Front Pharmacol 12:643972. https://doi.org/10.3389/fphar.2021.643972
  74. Rebourcet D, Darbey A, Monteiro A et al (2017) Sertoli cell number defines and predicts germ and leydig cell population sizes in the adult mouse testis. Endocrinology 158:2955-2969. https://doi.org/10.1210/en.2017-00196
  75. Acharya UR, Mishra M, Patro J, Panda MK (2008) Effect of vitamins C and E on spermatogenesis in mice exposed to cadmium. Reprod Toxicol 25:84-88. https://doi.org/10.1016/j.reprotox.2007.10.004
  76. De Franciscis P, Ianniello R, Labriola D et al (2015) Environmental pollution due to cadmium: measure of semen quality as a marker of exposure and correlation with reproductive potential. Clin Exp Obstet Gynecol 42:767-770 https://doi.org/10.12891/ceog3029.2015
  77. Ronis MJ, Badger TM, Shema SJ, Roberson PK, Shaikh F (1996) Reproductive toxicity and growth effects in rats exposed to lead at different periods during development. Toxicol Appl Pharmacol 136:361-371. https://doi.org/10.1006/taap.1996.0044
  78. Hamadouche NA, Nesrine S, Abdelkeder A (2013) Lead toxicity and the hypothalamic-pituitary-testicular axis. Notulae Scientia Biologicae 5:1-6. https://doi.org/10.15835/nsb518038
  79. Saxena DK, Hussain T, Lal B, Chandra SV (1986) Lead induced testicular dysfunction in weaned rats. Ind Health 24:105-109. https://doi.org/10.2486/indhealth.24.105
  80. Oliveira H, Spano M, Santos C, Pereira ML (2009) Lead chloride affects sperm motility and acrosome reaction in mice: lead affects mice sperm motility and acrosome reaction. Cell Biol Toxicol 25:341-353. https://doi.org/10.1007/s10565-008-9088-4
  81. Pandya C, Pillai P, Nampoothiri LP, Bhatt N, Gupta S, Gupta S (2012) Effect of lead and cadmium co-exposure on testicular steroid metabolism and antioxidant system of adult male rats. Andrologia 44 Suppl 1:813-822. https://doi.org/10.1111/j.1439-0272.2010.01137.x
  82. Wiebe JP, Salhanick AI, Myers KI (1983) On the mechanism of action of lead in the testis: In vitro suppresion of FSH receptors, cyclic AMP and steroidogenesis. Life Sci 32:1997-2005. https://doi.org/10.1016/0024-3205(83)90051-6
  83. Staessen JA, Nawrot T, Hond ED et al (2001) Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers. Lancet 357:1660-1669. https://doi.org/10.1016/s0140-6736(00)04822-4
  84. Sokol RZ, Wang S, Wan YJ, Stanczyk FZ, Gentzschein E, Chapin RE (2002) Long-term, low-dose lead exposure alters the gonadotropin-releasing hormone system in the male rat. Environ Health Perspect 110:871-874. https://doi.org/10.1289/ehp.02110871
  85. Ishizuka M, Ohtsuka E, Inoue A et al (2016) Abnormal spermatogenesis and male infertility in testicular zinc finger protein Zfp318-knockout mice. Dev Growth Differ 58:600-608. https://doi.org/10.1111/dgd.12301
  86. Wu J, Wu S, Xie Y et al (2015) Zinc protects sperm from being damaged by reactive oxygen species in assisted reproduction techniques. Reprod Biomed Online 30:334-339. https://doi.org/10.1016/j.rbmo.2014.12.008
  87. Fatima P, Hossain MM, Rahman D et al (2015) Association of blood and semen lead and zinc level with semen parameter in the male partner of infertile couple. Mymensingh Med J 24:537-541
  88. de Araujo Ramos AT, Diamante MAS, de Almeida LC, Dolder H, de Souza PF (2017) Morphological and morphometrical changes on adult Wistar rat testis caused by chronic sodium arsenite exposure. Environ Sci Pollut Res Int 24:27905-27912. https://doi.org/10.1007/s11356-017-0200-2
  89. Balduit A, Mangogna A, Agostinis C et al (2020) Zinc oxide exerts anti-inflammatory properties on human placental cells. Nutrients 12:1822. https://doi.org/10.3390/nu12061822
  90. Said L, Banni M, Kerkeni A, Said K, Messaoudi I (2010) Influence of combined treatment with zinc and selenium on cadmium induced testicular pathophysiology in rat. Food Chem Toxicol 48:2759-2765. https://doi.org/10.1016/j.fct.2010.07.003
  91. Sugiura Y, Kashiba M, Maruyama K et al (2005) Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes. Antioxid Redox Signal 7:781-787. https://doi.org/10.1089/ars.2005.7.781
  92. Asadi N, Bahmani M, Kheradmand A, Rafeian-Kopaei M (2017) The impact of oxidative stress on testicular function and the role of antioxidants in improving it: a review. J Clin Diagn Res 11:IE01. https://doi.org/10.7860/JCDR/2017/23927.9886
  93. Picon-Pages P, Garcia-Buendia J, Munoz FJ (2019) Functions and dysfunctions of nitric oxide in brain. Biochim Biophys Acta Mol Basis Dis 1865:1949-1967. https://doi.org/10.1016/j.bbadis.2018.11.007
  94. Madhurantakam C, Duru AD, Sandalova T, Webb JR, Achour A (2012) Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex. PLoS One 7:e32805
  95. Thomas DD (2015) Breathing new life into nitric oxide signaling: a brief overview of the interplay between oxygen and nitric oxide. Redox Biol 5:225-233. https://doi.org/10.1016/j.redox.2015.05.002
  96. Shafk NM, El Batsh MM (2016) Protective effects of combined selenium and Punica granatum treatment on some inflammatory and oxidative stress markers in arsenic-induced hepatotoxicity in rats. Biol Trace Elem Res 169:121-128. https://doi.org/10.1007/s12011-015-0397-1
  97. Blaser H, Dostert C, Mak TW, Brenner D (2016) TNF and ROS crosstalk in inflammation. Trends Cell Biol 26:249-261. https://doi.org/10.1016/j.tcb.2015.12.002
  98. Morgan MJ, Liu ZG (2010) Reactive oxygen species in TNFalpha-induced signaling and cell death. Mol Cells 30:1-12. https://doi.org/10.1007/s10059-010-0105-0
  99. Didion SP (2017) Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature. Int J Mol Sci 18:2563. https://doi.org/10.3390/ijms18122563
  100. Khanna S, Lakhera PC, Khandelwal S (2011) Interplay of early biochemical manifestations by cadmium insult in sertoli-germ coculture: an in vitro study. Toxicology 287:46-53. https://doi.org/10.1016/j.tox.2011.05.013
  101. Rotimi DE, Ojo OA, Olaolu TD, Adeyemi OS (2022) Exploring Nrf2 as a therapeutic target in testicular dysfunction. Cell Tissue Res 390:23-33. https://doi.org/10.1007/s00441-022-03664-3
  102. Buha A, Baralic K, Djukic-Cosic D et al (2021) The role of toxic metals and metalloids in Nrf2 signaling. Antioxidants (Basel) 10:630. https://doi.org/10.3390/antiox10050630
  103. Ighodaro OM, Akinloye OA (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alex J Med 54:287-293. https://doi.org/10.1016/j.ajme.2017.09.001
  104. Messaoudi I, El Heni J, Hammouda F, Said K, Kerkeni A (2009) Protective effects of selenium, zinc, or their combination on cadmium-induced oxidative stress in rat kidney. Biol Trace Elem Res 130:152-161. https://doi.org/10.1007/s12011-009-8324-y
  105. Li B, Cui W, Tan Y et al (2014) Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition. J Cell Mol Med 18:895-906. https://doi.org/10.1111/jcmm.12239
  106. Bao RK, Zheng SF, Wang XY (2017) Selenium protects against cadmium-induced kidney apoptosis in chickens by activating the PI3K/AKT/Bcl-2 signaling pathway. Environ Sci Pollut Res Int 24:20342-20353. https://doi.org/10.1007/s11356-017-9422-6
  107. Raut S, Deshpande S, Balasinor NH (2019) Unveiling the role of prolactin and its receptor in male reproduction. Horm Metab Res 51:215-219. https://doi.org/10.1055/a-0859-1144
  108. Anka AU, Usman AB, Kaoje AN et al (2022) Potential mechanisms of some selected heavy metals in the induction of inflammation and autoimmunity. Eur J Inflamm 20:1721727X221122719. https://doi.org/10.1177/1721727x221122719
  109. Martin-Hidalgo D, Bragado MJ, Batista AR, Oliveira PF, Alves MG (2019) Antioxidants and male fertility: from molecular studies to clinical evidence. Antioxidants (Basel) 8:89. https://doi.org/10.3390/antiox8040089
  110. He Y, Zou L, Luo W et al (2020) Heavy metal exposure, oxidative stress and semen quality: exploring associations and mediation effects in reproductive-aged men. Chemosphere 244:125498. https://doi.org/10.1016/j.chemosphere.2019.125498