Abstract
Cadmium (Cd) has been widely studied as an environmental pollutant for many years. Numerous studies have reported that Cd exposure causes damage to the heart, liver, kidneys, and thyroid in vivo. The emerging evidence suggests that Cd exposure induces damage on male reproductive system, which is related to oxidative stress, inflammation, steroidogenesis disruption, and epigenetics. Current preclinical animal studies have confirmed a large number of proteins and intracellular signaling pathways involved in the pathological process of Cd-induced male reproductive damage and potential measures for prophylaxis and treatment, which primarily include antioxidants, anti-inflammatory agents, and essential ion supplement. However, explicit pathogenesis and effective treatments remain uncertain. This review collects data from the literatures, discusses the underlying mechanisms of Cd-induced toxicity on male reproductive function, and summarizes evidence that may provide guidance for the treatment and prevention of Cd-induced male reproductive toxicity.
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Abbreviations
- 17β-HSD:
-
17β-Hydroxysteroid dehydrogenase
- 3β-HSD:
-
3β-Hydroxysteroid dehydrogenase
- ABCG2:
-
ATP-binding cassette G2
- AR:
-
Androgen receptor
- BTB:
-
Blood-testis barrier
- BW:
-
Body weight
- CatSper:
-
Sperm-specific cation channel
- Cd:
-
Cadmium
- DAX-1:
-
Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1
- DMT:
-
Divalent metal receptor
- DNMT:
-
DNA methyltransferase
- EDTA:
-
Ethylenediaminetetraacetic acid
- FSH:
-
Follicle stimulating hormone
- GPx:
-
Glutathione peroxidase
- H3K9me2:
-
Histone H3 lysine 9 dimethylation
- HPG:
-
Hypothalamic-pituitary-gonadal
- ICAM2:
-
Intercellular adhesion molecule 2
- LH:
-
Luteinizing hormone
- LHR:
-
Luteinizing hormone receptor
- lncRNA:
-
Long non-coding RNA
- LPO:
-
Lipid peroxidation
- MDA:
-
Malondialdehyde
- MMP:
-
Mitochondrial membrane potential
- MRL:
-
Minimum risk level
- MT:
-
Metallothionein
- NAC:
-
N-acetylcysteine
- NLRP3:
-
Nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3
- PMCA:
-
Plasma membrane Ca2+-ATPase
- QE:
-
Quercetin
- RGN:
-
Regucalcin
- ROS:
-
Reactive oxygen species
- Se:
-
Selenium
- SelP:
-
Selenoprotein P
- SOD:
-
Superoxide dismutase
- Star:
-
Steroidogenic acute regulatory protein
- STAT3:
-
Signal transducer and activator of transcription 3
- TBARS:
-
Thiobarbituric acid reactive substances
- ZIP:
-
Zinc finger protein
- Zn:
-
Zinc
References
Abarikwu SO, Iserhienrhien BO, Badejo TA (2013) Rutin- and selenium-attenuated cadmium-induced testicular pathophysiology in rats. Hum Exp Toxicol 32:395–406. https://doi.org/10.1177/0960327112472995
Abarikwu SO, Olufemi PD, Lawrence CJ et al (2017) Rutin, an antioxidant flavonoid, induces glutathione and glutathione peroxidase activities to protect against ethanol effects in cadmium-induced oxidative stress in the testis of adult rats. Andrologia 49. https://doi.org/10.1111/and.12696
Aktas C, Kanter M, Erboga M et al (2012) Anti-apoptotic effects of curcumin on cadmium-induced apoptosis in rat testes. Toxicol Ind Health 28:122–130. https://doi.org/10.1177/0748233711407242
Al-Azemi M, Omu FE, Kehinde EO et al (2010) Lithium protects against toxic effects of cadmium in the rat testes. J Assist Reprod Genet 27:469–476. https://doi.org/10.1007/s10815-010-9426-3
Alli LA (2015) Blood level of cadmium and lead in occupationally exposed persons in Gwagwalada, Abuja, Nigeria. Interdiscip Toxicol 8:146–150. https://doi.org/10.1515/intox-2015-0022
Alsalman ARS, Almashhedy LA, Alta'ee AH et al (2020) Effect of zinc supplementation on urate pathway enzymes in spermatozoa and seminal plasma of Iraqi asthenozoospermic patients: a randomized controlled trial. Int J Fertil Steril 13:315–323. https://doi.org/10.22074/ijfs.2020.5760
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
Andreucci A, Mocevic E, Jonsson BA et al (2015) Cadmium may impair prostate function as measured by prostate specific antigen in semen: a cross-sectional study among European and Inuit men. Reprod Toxicol 53:33–38. https://doi.org/10.1016/j.reprotox.2015.01.010
Aoshima K (2012) Itai-itai disease: cadmium-induced renal tubular osteomalacia. Nihon Eiseigaku Zasshi 67:455–463. https://doi.org/10.1265/jjh.67.455
Ardestani Zadeh A, Arab D, Kia NS et al (2019) The role of vitamin E - selenium - folic acid supplementation in improving sperm parameters after varicocelectomy: a randomized clinical trial. Urol J 16:495–500. https://doi.org/10.22037/uj.v0i0.4653
Ates I, Suzen HS, Aydin A et al (2004) The oxidative DNA base damage in testes of rats after intraperitoneal cadmium injection. Biometals 17:371–377. https://doi.org/10.1023/b:biom.0000029416.95488.5f
ATSDR (2012) ToxGuide™ for cadmium. https://www.atsdr.cdc.gov/toxguides/toxguide-5.pdf. Accessed 11 Nov 2020
ATSDR (2020) Minimal risk levels (MRLs) for hazardous substances. https://www.atsdr.cdc.gov/toxguides/toxguide-5.pdf. Accessed 11 Nov 2020
Babaknejad N, Bahrami S, Moshtaghie AA et al (2018) Cadmium testicular toxicity in male Wistar rats: protective roles of zinc and magnesium. Biol Trace Elem Res 185:106–115. https://doi.org/10.1007/s12011-017-1218-5
Badr GM, Elsawy H, Sedky A et al (2019) Protective effects of quercetin supplementation against short-term toxicity of cadmium-induced hematological impairment, hypothyroidism, and testicular disturbances in albino rats. Environ Sci Pollut Res Int 26:8202–8211. https://doi.org/10.1007/s11356-019-04276-1
Bashir N, Shagirtha K, Manoharan V et al (2019) The molecular and biochemical insight view of grape seed proanthocyanidins in ameliorating cadmium-induced testes-toxicity in rat model: implication of PI3K/Akt/Nrf-2 signaling. Biosci Rep 39. https://doi.org/10.1042/BSR20180515
Basu Mallik S, Jayashree BS, Shenoy RR (2018) Epigenetic modulation of macrophage polarization- perspectives in diabetic wounds. J Diabetes Complicat 32:524–530. https://doi.org/10.1016/j.jdiacomp.2018.01.015
Beigi Harchegani A, Dahan H, Tahmasbpour E et al (2020) Effects of zinc deficiency on impaired spermatogenesis and male infertility: the role of oxidative stress, inflammation and apoptosis. Hum Fertil (Camb) 23:5–16. https://doi.org/10.1080/14647273.2018.1494390
Bellinger (2004) WHO food additives series: 52-cadmium. http://www.inchem.org/documents/jecfa/jecmono/v52je22.htm. Accessed 11 Nov 2020
Bench G, Corzett MH, Martinelli R et al (1999) Cadmium concentrations in the testes, sperm, and spermatids of mice subjected to long-term cadmium chloride exposure. Cytometry 35:30–36. https://doi.org/10.1002/(sici)1097-0320(19990101)35:1<30::aid-cyto5>3.3.co;2-d
Blanco A, Moyano R, Molina Lopez AM et al (2010) Preneoplastic and neoplastic changes in the Leydig cells population in mice exposed to low doses of cadmium. Toxicol Ind Health 26:451–457. https://doi.org/10.1177/0748233710371111
Blum JL, Edwards JR, Prozialeck WC et al (2015) Effects of maternal exposure to cadmium oxide nanoparticles during pregnancy on maternal and offspring kidney injury markers using a murine model. J Toxicol Environ Health A 78:711–724. https://doi.org/10.1080/15287394.2015.1026622
Boitani C, Puglisi R (2008) Selenium, a key element in spermatogenesis and male fertility. Adv Exp Med Biol 636:65–73. https://doi.org/10.1007/978-0-387-09597-4_4
Bomhard E, Vogel O, Loser E (1987) Chronic effects on single and multiple oral and subcutaneous cadmium administrations on the testes of Wistar rats. Cancer Lett 36:307–315. https://doi.org/10.1016/0304-3835(87)90024-3
Bonda E, Wlostowski T, Krasowska A (2004) 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 17:615–624. https://doi.org/10.1007/s10534-004-1226-8
Brooks SA, Fry RC (2017) Cadmium inhibits placental trophoblast cell migration via miRNA regulation of the transforming growth factor beta (TGF-beta) pathway. Food Chem Toxicol 109:721–726. https://doi.org/10.1016/j.fct.2017.07.059
Bu T, Mi Y, Zeng W et al (2011) Protective effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice. Anat Rec (Hoboken) 294:520–526. https://doi.org/10.1002/ar.21317
Chakraborty S, Gang S, Sengupta M (2014) Functional status of testicular macrophages in an immunopriviledged niche in cadmium intoxicated murine testes. Am J Reprod Immunol 72:14–21. https://doi.org/10.1111/aji.12224
Chemek M, Mimouna SB, Boughammoura S et al (2016) Protective role of zinc against the toxicity induced by exposure to cadmium during gestation and lactation on testis development. Reprod Toxicol 63:151–160. https://doi.org/10.1016/j.reprotox.2016.06.005
Chen H, Lu Y, Cao Z et al (2016) Cadmium induces NLRP3 inflammasome-dependent pyroptosis in vascular endothelial cells. Toxicol Lett 246:7–16. https://doi.org/10.1016/j.toxlet.2016.01.014
Chen N, Su P, Wang M et al (2018) Ascorbic acid inhibits cadmium-induced disruption of the blood-testis barrier by regulating oxidative stress-mediated p38 MAPK pathways. Environ Sci Pollut Res Int 25:21713–21720. https://doi.org/10.1007/s11356-018-2138-4
Cherian MG (1983) Absorption and tissue distribution of cadmium in mice after chronic feeding with cadmium chloride and cadmium-metallothionein. Bull Environ Contam Toxicol 30:33–36. https://doi.org/10.1007/BF01610095
Chinyere Nsonwu-Anyanwu A, Raymond Ekong E, Jeremiah Offor S et al (2019) Heavy metals, biomarkers of oxidative stress and changes in sperm function: a case-control study. Int J Reprod Biomed 17. https://doi.org/10.18502/ijrm.v17i3.4515
Clark JT, Jimenez B, Evans SL et al (1994) Cadmium-induced sexual dysfunction does not involve increased hepatic metabolism of testosterone nor increased circulating levels of corticosterone. Physiol Behav 56:975–981. https://doi.org/10.1016/0031-9384(94)90332-8
Correia S, Vaz CV, Silva AM et al (2017) Regucalcin counteracts tert-butyl hydroperoxide and cadmium-induced oxidative stress in rat testis. J Appl Toxicol 37:159–166. https://doi.org/10.1002/jat.3333
Cowley M, Skaar DA, Jima DD et al (2018) Effects of cadmium exposure on DNA methylation at imprinting control regions and genome-wide in mothers and newborn children. Environ Health Perspect 126:037003. https://doi.org/10.1289/EHP2085
Croxford TP, McCormick NH, Kelleher SL (2011) Moderate zinc deficiency reduces testicular Zip6 and Zip10 abundance and impairs spermatogenesis in mice. J Nutr 141:359–365. https://doi.org/10.3945/jn.110.131318
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. Oxidative Med Cell Longev 2017:3405089. https://doi.org/10.1155/2017/3405089
Da Costa R, Botana D, Pinero S et al (2016) Cadmium inhibits motility, activities of plasma membrane Ca(2+)-ATPase and axonemal dynein-ATPase of human spermatozoa. Andrologia 48:464–469. https://doi.org/10.1111/and.12466
Deng YF, Weng ZW, Liang AJ et al (2019) Shenjing Guben pills for repairing testicular spermatogenic injury induced by oxidative stress in rats. Zhonghua Nan Ke Xue 25:1118–1125
Dharmadasa P, Kim N, Thunders M (2017) Maternal cadmium exposure and impact on foetal gene expression through methylation changes. Food Chem Toxicol 109:714–720. https://doi.org/10.1016/j.fct.2017.09.002
Dhooge W, Stuyvaert S, Kaufman JM et al (2001) Observations as to male fertility in the Flemish environment and health studies. Folia Histochem Cytobiol 39(Suppl 2):38–39
Elbaghdady HAM, Alwaili MA, El-Demerdash RS (2018) Regenerative potential of bone marrow mesenchymal stem cells on cadmium chloride-induced hepato-renal injury and testicular dysfunction in Sprague dawley rats. Ecotoxicol Environ Saf 164:41–49. https://doi.org/10.1016/j.ecoenv.2018.07.019
Elblehi SS, El Euony OI, El-Nahas AF (2019) Partial ameliorative effect of Moringa leaf ethanolic extract on the reproductive toxicity and the expression of steroidogenic genes induced by subchronic cadmium in male rats. Environ Sci Pollut Res Int 26:23306–23318. https://doi.org/10.1007/s11356-019-05607-y
EPA (1998) Series 870 - health effects test guidelines. https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances/series-870-health-effects-test-guidelines. Accessed 1 Dec 2020
Erboga M, Kanter M (2016) Effect of cadmium on trophoblast cell proliferation and apoptosis in different gestation periods of rat placenta. Biol Trace Elem Res 169:285–293. https://doi.org/10.1007/s12011-015-0439-8
Fallah A, Mohammad-Hasani A, Colagar AH (2018) Zinc is an essential element for male fertility: a review of Zn roles in men’s health, germination, sperm quality, and fertilization. J Reprod Infertil 19:69–81
Fang Y, Xiang Y, Lu X et al (2020) Epigenetic dysregulation of Mdr1b in the blood-testis barrier contributes to dyszoospermia in mice exposed to cadmium. Ecotoxicol Environ Saf 190:110142. https://doi.org/10.1016/j.ecoenv.2019.110142
Faroon O, Ashizawa A, Wright S et al (2012). Toxicological profile for cadmium. Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles, Atlanta, GA. https://www.ncbi.nlm.nih.gov/pubmed/24049863. Accessed 11 Nov 2020
Feng J, Chen S, Wang Y et al (2019) Maternal exposure to cadmium impairs cognitive development of male offspring by targeting the Coronin-1a signaling pathway. Chemosphere 225:765–774. https://doi.org/10.1016/j.chemosphere.2019.03.094
Fouad AA, Jresat I (2013) Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats. Fundam Clin Pharmacol 27:152–160. https://doi.org/10.1111/j.1472-8206.2011.00974.x
Fouad AA, Jresat I (2015) Thymoquinone therapy abrogates toxic effect of cadmium on rat testes. Andrologia 47:417–426. https://doi.org/10.1111/and.12281
Fouad AA, Abdel-Aziz AM, Hamouda AAH (2020) Diacerein downregulates NLRP3/Caspase-1/IL-1beta and IL-6/STAT3 pathways of inflammation and apoptosis in a rat model of cadmium testicular toxicity. Biol Trace Elem Res 195:499–505. https://doi.org/10.1007/s12011-019-01865-6
Gao F, Zhang P, Zhang H et al (2017) Dysregulation of long noncoding RNAs in mouse testes and spermatozoa after exposure to cadmium. Biochem Biophys Res Commun 484:8–14. https://doi.org/10.1016/j.bbrc.2017.01.091
Goyal T, Mitra P, Singh P et al (2020) Assessement of blood lead and cadmium levels in occupationally exposed workers of Jodhpur, Rajasthan. Indian J Clin Biochem. https://doi.org/10.1007/s12291-020-00878-6
Gunnarsson D, Nordberg G, Lundgren P et al (2003) Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats. Toxicology 183:57–63. https://doi.org/10.1016/s0300-483x(02)00440-7
Habib R, Wahdan SA, Gad AM et al (2019) Infliximab abrogates cadmium-induced testicular damage and spermiotoxicity via enhancement of steroidogenesis and suppression of inflammation and apoptosis mediators. Ecotoxicol Environ Saf 182:109398. https://doi.org/10.1016/j.ecoenv.2019.109398
Hawkes WC, Alkan Z, Wong K (2009) Selenium supplementation does not affect testicular selenium status or semen quality in North American men. J Androl 30:525–533. https://doi.org/10.2164/jandrol.108.006940
He L, Wang B, Hay EB et al (2009) Discovery of ZIP transporters that participate in cadmium damage to testis and kidney. Toxicol Appl Pharmacol 238:250–257. https://doi.org/10.1016/j.taap.2009.02.017
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
Henkel R, Sandhu IS, Agarwal A (2019) The excessive use of antioxidant therapy: a possible cause of male infertility? Andrologia 51:e13162. https://doi.org/10.1111/and.13162
Hu H, Lu X, Cen X et al (2014) RNA-Seq identifies key reproductive gene expression alterations in response to cadmium exposure. Biomed Res Int 2014:529271. https://doi.org/10.1155/2014/529271
Huang G, Yuan M, Zhang J et al (2016) IL-6 mediates differentiation disorder during spermatogenesis in obesity-associated inflammation by affecting the expression of Zfp637 through the SOCS3/STAT3 pathway. Sci Rep 6:28012. https://doi.org/10.1038/srep28012
Huang Y, Zhu J, Li H et al (2020) Cadmium exposure during prenatal development causes testosterone disruption in multigeneration via SF-1 signaling in rats. Food Chem Toxicol 135:110897. https://doi.org/10.1016/j.fct.2019.110897
Hudson KM, Belcher SM, Cowley M (2019) Maternal cadmium exposure in the mouse leads to increased heart weight at birth and programs susceptibility to hypertension in adulthood. Sci Rep 9:13553. https://doi.org/10.1038/s41598-019-49807-5
Ikeda M, Nakatsuka H, Watanabe T et al (2015) Estimation of daily cadmium intake from cadmium in blood or cadmium in urine. Environ Health Prev Med 20:455–459. https://doi.org/10.1007/s12199-015-0479-x
Jahan S, Zahra A, Irum U et al (2014) Protective effects of different antioxidants against cadmium induced oxidative damage in rat testis and prostate tissues. Syst Biol Reprod Med 60:199–205. https://doi.org/10.3109/19396368.2014.912363
Jamilaldin Fatemi S, Saljooghi AS, Balooch FD et al (2011) Chelation of cadmium by combining deferasirox and deferiprone in rats. Toxicol Ind Health 27:371–377. https://doi.org/10.1177/0748233710388451
Jarup L, Berglund M, Elinder CG et al (1998) Health effects of cadmium exposure--a review of the literature and a risk estimate. Scand J Work Environ Health 24(Suppl 1):1–51
Jasperson KW, Tuohy TM, Neklason DW et al (2010) Hereditary and familial colon cancer. Gastroenterology 138:2044–2058. https://doi.org/10.1053/j.gastro.2010.01.054
Jeong KS, Park H, Ha E et al (2015) Performance IQ in children is associated with blood cadmium concentration in early pregnancy. J Trace Elem Med Biol 30:107–111. https://doi.org/10.1016/j.jtemb.2014.11.007
Ji YL, Wang H, Liu P et al (2011) Effects of maternal cadmium exposure during late pregnant period on testicular steroidogenesis in male offspring. Toxicol Lett 205:69–78. https://doi.org/10.1016/j.toxlet.2011.05.233
Ji YL, Wang H, Zhang C et al (2013) N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes. Asian J Androl 15:290–296. https://doi.org/10.1038/aja.2012.129
Jin X, Jia T, Liu R et al (2018) The antagonistic effect of selenium on cadmium-induced apoptosis via PPAR-gamma/PI3K/Akt pathway in chicken pancreas. J Hazard Mater 357:355–362. https://doi.org/10.1016/j.jhazmat.2018.06.003
Kamel M, Razek A, Ahmed K et al (2011) Exposure of adult male rats to cadmium: assessment of sexual behaviour, fertility, aggression as well as anxiety like behaviour with special reference to biochemical and pathological alterations. Life Science Journal 8:106–119
Keck C, Bramkamp G, Behre HM et al (1995) Lack of correlation between cadmium in seminal plasma and fertility status of nonexposed individuals and two cadmium-exposed patients. Reprod Toxicol 9:35–40. https://doi.org/10.1016/0890-6238(94)00053-y
Khanna S, Mitra S, Lakhera PC et al (2016) N-acetylcysteine effectively mitigates cadmium-induced oxidative damage and cell death in Leydig cells in vitro. Drug Chem Toxicol 39:74–80. https://doi.org/10.3109/01480545.2015.1028068
Kippler M, Bottai M, Georgiou V et al (2016) Impact of prenatal exposure to cadmium on cognitive development at preschool age and the importance of selenium and iodine. Eur J Epidemiol 31:1123–1134. https://doi.org/10.1007/s10654-016-0151-9
Kiziler AR, Aydemir B, Onaran I et al (2007) High levels of cadmium and lead in seminal fluid and blood of smoking men are associated with high oxidative stress and damage in infertile subjects. Biol Trace Elem Res 120:82–91. https://doi.org/10.1007/s12011-007-8020-8
Koizumi N, Murata K, Hayashi C et al (2008) High cadmium accumulation among humans and primates: comparison across various mammalian species--a study from Japan. Biol Trace Elem Res 121:205–214. https://doi.org/10.1007/s12011-007-8048-9
Krasovskii GN, Varshavskaya SP, Borisov AI (1976) Toxic and gonadotropic effects of cadmium and boron relative to standards for these substances in drinking water. Environ Health Perspect 13:69–75. https://doi.org/10.1289/ehp.761369
Lafuente A, Gonzalez-Carracedo A, Romero A et al (2004) Cadmium exposure differentially modifies the circadian patterns of norepinephrine at the median eminence and plasma LH, FSH and testosterone levels. Toxicol Lett 146:175–182. https://doi.org/10.1016/j.toxlet.2003.10.004
Li CJ, Yeh CY, Chen RY et al (2015) Biomonitoring of blood heavy metals and reproductive hormone level related to low semen quality. J Hazard Mater 300:815–822. https://doi.org/10.1016/j.jhazmat.2015.08.027
Li M, Liu C, Yang L et al (2016a) G9a-mediated histone methylation regulates cadmium-induced male fertility damage in pubertal mice. Toxicol Lett 252:11–21. https://doi.org/10.1016/j.toxlet.2016.04.004
Li R, Luo X, Li L et al (2016b) The protective effects of melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis. Biol Trace Elem Res 170:152–164. https://doi.org/10.1007/s12011-015-0449-6
Li X, Wang L, Li Y et al (2016c) Tyrosine phosphorylation of dihydrolipoamide dehydrogenase as a potential cadmium target and its inhibitory role in regulating mouse sperm motility. Toxicology 357–358:52–64. https://doi.org/10.1016/j.tox.2016.06.003
Li Y, Wu J, Zhou W et al (2016d) Association between environmental exposure to cadmium and human semen quality. Int J Environ Health Res 26:175–186. https://doi.org/10.1080/09603123.2015.1061115
Li R, Zhao L, Li L et al (2017) A preliminary study about the potential effects of heavy metals on the human male reproductive parameters in HIV-infected population in China. Biol Trace Elem Res 180:39–47. https://doi.org/10.1007/s12011-017-0998-y
Ling LB, Chang Y, Liu CW et al (2017) Oxidative stress intensity-related effects of cadmium (Cd) and paraquat (PQ) on UV-damaged-DNA binding and excision repair activities in zebrafish (Danio rerio) embryos. Chemosphere 167:10–18. https://doi.org/10.1016/j.chemosphere.2016.09.068
Liu L, Zhou L, Hu S et al (2016a) Down-regulation of ABCG2 and ABCB4 transporters in the placenta of rats exposed to cadmium. Oncotarget 7:38154–38163. https://doi.org/10.18632/oncotarget.9415
Liu XR, Wang YY, Fan HR et al (2016b) Preventive effects of beta-cryptoxanthin against cadmium-induced oxidative stress in the rat testis. Asian J Androl 18:920–924. https://doi.org/10.4103/1008-682X.173449
Liu D, Wan J, Liu Z et al (2020) Determination of cadmium induced acute and chronic reproductive toxicity with Raman spectroscopy. Lasers Med Sci. https://doi.org/10.1007/s10103-020-02976-6
Marano KM, Naufal ZS, Kathman SJ et al (2012) Cadmium exposure and tobacco consumption: biomarkers and risk assessment. Regul Toxicol Pharmacol 64:243–252. https://doi.org/10.1016/j.yrtph.2012.07.008
Martin MB, Voeller HJ, Gelmann EP et al (2002) Role of cadmium in the regulation of AR gene expression and activity. Endocrinology 143:263–275. https://doi.org/10.1210/endo.143.1.8581
McCarty MF (2012) Zinc and multi-mineral supplementation should mitigate the pathogenic impact of cadmium exposure. Med Hypotheses 79:642–648. https://doi.org/10.1016/j.mehy.2012.07.043
Medina MF, Arrieta MC, Villafane MN et al (2017) Early signs of toxicity in testes and sperm of rats exposed to low cadmium doses. Toxicol Ind Health 33:576–587. https://doi.org/10.1177/0748233716689524
Meeker JD, Rossano MG, Protas B et al (2008) Cadmium, lead, and other metals in relation to semen quality: human evidence for molybdenum as a male reproductive toxicant. Environ Health Perspect 116:1473–1479. https://doi.org/10.1289/ehp.11490
Meeker JD, Rossano MG, Protas B et al (2010) Environmental exposure to metals and male reproductive hormones: circulating testosterone is inversely associated with blood molybdenum. Fertil Steril 93:130–140. https://doi.org/10.1016/j.fertnstert.2008.09.044
Mendiola J, Moreno JM, Roca M et al (2011) Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: a pilot study. Environ Health 10:6. https://doi.org/10.1186/1476-069X-10-6
Messaoudi I, Banni M, Said L et al (2010) Involvement of selenoprotein P and GPx4 gene expression in cadmium-induced testicular pathophysiology in rat. Chem Biol Interact 188:94–101. https://doi.org/10.1016/j.cbi.2010.07.012
Mikowska M, Dziublinska B, Swiergosz-Kowalewska R (2018) Variation of metallothionein I and II gene expression in the bank vole (Clethrionomys glareolus) under environmental zinc and cadmium exposure. Arch Environ Contam Toxicol 75:66–74. https://doi.org/10.1007/s00244-017-0485-7
Minutoli L, Micali A, Pisani A et al (2015) Flavocoxid protects against cadmium-induced disruption of the blood-testis barrier and improves testicular damage and germ cell impairment in mice [corrected]. Toxicol Sci 148:311–329. https://doi.org/10.1093/toxsci/kfv185
Mishra RK, Jain A, Singh SK (2018) Profertility effects of Shilajit on cadmium-induced infertility in male mice. Andrologia 50:e13064. https://doi.org/10.1111/and.13064
Mitra S, Varghese AC, Mandal S et al (2020) Lead and cadmium exposure induces male reproductive dysfunction by modulating the expression profiles of apoptotic and survival signal proteins in tea-garden workers. Reprod Toxicol. https://doi.org/10.1016/j.reprotox.2020.09.006
Momeni HR, Eskandari N (2020) Curcumin protects the testis against cadmium-induced histopathological damages and oxidative stress in mice. Hum Exp Toxicol 39:653–661. https://doi.org/10.1177/0960327119895564
Moslemi MK, Tavanbakhsh S (2011) Selenium-vitamin E supplementation in infertile men: effects on semen parameters and pregnancy rate. Int J Gen Med 4:99–104. https://doi.org/10.2147/IJGM.S16275
Mouro VGS, Martins ALP, Silva J et al (2019) Subacute testicular toxicity to cadmium exposure intraperitoneally and orally. Oxidative Med Cell Longev 2019:3429635. https://doi.org/10.1155/2019/3429635
Mouro VGS, Siman VA, da Silva J et al (2020) Cadmium-induced testicular toxicity in mice: subacute and subchronic route-dependent effects. Biol Trace Elem Res 193:466–482. https://doi.org/10.1007/s12011-019-01731-5
Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31. https://doi.org/10.4103/0976-0105.177703
Nair A, Morsy MA, Jacob S (2018) Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res 79:373–382. https://doi.org/10.1002/ddr.21461
Nakayama SMM, Nakata H, Ikenaka Y et al (2019) One year exposure to Cd- and Pb-contaminated soil causes metal accumulation and alteration of global DNA methylation in rats. Environ Pollut 252:1267–1276. https://doi.org/10.1016/j.envpol.2019.05.038
Nicoglou A, Merlin F (2017) Epigenetics: a way to bridge the gap between biological fields. Stud Hist Phil Biol Biomed Sci 66:73–82. https://doi.org/10.1016/j.shpsc.2017.10.002
Nishijo M, Nakagawa H, Suwazono Y et al (2017) Causes of death in patients with Itai-itai disease suffering from severe chronic cadmium poisoning: a nested case-control analysis of a follow-up study in Japan. BMJ Open 7:e015694. https://doi.org/10.1136/bmjopen-2016-015694
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
Oguzturk H, Ciftci O, Aydin M et al (2012) Ameliorative effects of curcumin against acute cadmium toxicity on male reproductive system in rats. Andrologia 44:243–249. https://doi.org/10.1111/j.1439-0272.2012.01273.x
Ohta H, Qi Y, Ohba K et al (2019) Role of metallothionein-like cadmium-binding protein (MTLCdBP) in the protective mechanism against cadmium toxicity in the testis. Ind Health 57:570–579. https://doi.org/10.2486/indhealth.2018-0177
Olson GE, Winfrey VP, Hill KE et al (2004) Sequential development of flagellar defects in spermatids and epididymal spermatozoa of selenium-deficient rats. Reproduction 127:335–342. https://doi.org/10.1530/rep.1.00103
Ono H, Funakoshi T, Shimada H et al (1997) Comparative effects of disulfiram and diethyldithiocarbamate against testicular toxicity in rats caused by acute exposure to cadmium. J Toxicol Environ Health 50:389–399. https://doi.org/10.1080/009841097160429
Pillai P, Pandya C, Gupta S et al (2010) Biochemical and molecular effects of gestational and lactational coexposure to lead and cadmium on ovarian steroidogenesis are associated with oxidative stress in F1 generation rats. J Biochem Mol Toxicol 24:384–394. https://doi.org/10.1002/jbt.20351
Prasad AS (2014) Zinc is an antioxidant and anti-inflammatory agent: its role in human health. Front Nutr 1:14. https://doi.org/10.3389/fnut.2014.00014
Rajendar B, Bharavi K, Rao GS et al (2011) Protective effect of an aphrodisiac herb Tribulus terrestris Linn on cadmium-induced testicular damage. Indian J Pharmacol 43:568–573. https://doi.org/10.4103/0253-7613.84974
Ramos-Trevino J, Bassol-Mayagoitia S, Ruiz-Flores P et al (2017) In vitro evaluation of damage by heavy metals in tight and gap junctions of sertoli cells. DNA Cell Biol 36:829–836. https://doi.org/10.1089/dna.2017.3839
Rania Abdel Rahman E, Mohamed Elshabrawy G (2014) Effect of long term cadmium chloride exposure on testicular functions in male albino rats. Am J Anim Vet Sci 9. https://doi.org/10.3844/ajavsp.2014.182.188
Ren XM, Wang GG, Xu DQ et al (2012) The protection of selenium on cadmium-induced inhibition of spermatogenesis via activating testosterone synthesis in mice. Food Chem Toxicol 50:3521–3529. https://doi.org/10.1016/j.fct.2012.07.021
Riaz M, Mahmood Z, Shahid M et al (2016) Impact of reactive oxygen species on antioxidant capacity of male reproductive system. Int J Immunopathol Pharmacol 29:421–425. https://doi.org/10.1177/0394632015608994
Romano ME, Enquobahrie DA, Simpson C et al (2016) Maternal body burden of cadmium and offspring size at birth. Environ Res 147:461–468. https://doi.org/10.1016/j.envres.2016.02.029
Ronco AM, Montenegro M, Castillo P et al (2011) Maternal exposure to cadmium during gestation perturbs the vascular system of the adult rat offspring. Toxicol Appl Pharmacol 251:137–145. https://doi.org/10.1016/j.taap.2011.01.001
Sadasivam M, Ramatchandirin B, Balakrishnan S et al (2015) TNF-alpha-mediated suppression of Leydig cell steroidogenesis involves DAX-1. Inflamm Res 64:549–556. https://doi.org/10.1007/s00011-015-0835-8
Saha R, Roychoudhury S, Kar K et al (2019) Coenzyme Q10 ameliorates cadmium induced reproductive toxicity in male rats. Physiol Res 68:141–145. https://doi.org/10.33549/physiolres.934000
Said L, Banni M, Kerkeni A et al (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
Sankako MK, Garcia PC, Piffer RC et al (2012) Possible mechanism by which zinc protects the testicular function of rats exposed to cigarette smoke. Pharmacol Rep 64:1537–1546. https://doi.org/10.1016/s1734-1140(12)70951-9
Santana VP, Salles ES, Correa DE et al (2016) Long-term effects of perinatal exposure to low doses of cadmium on the prostate of adult male rats. Int J Exp Pathol 97:310–316. https://doi.org/10.1111/iep.12193
Schopfer J, Drasch G, Schrauzer GN (2010) Selenium and cadmium levels and ratios in prostates, livers, and kidneys of nonsmokers and smokers. Biol Trace Elem Res 134:180–187. https://doi.org/10.1007/s12011-010-8636-y
Sen Gupta R, Kim J, Gomes C et al (2004) Effect of ascorbic acid supplementation on testicular steroidogenesis and germ cell death in cadmium-treated male rats. Mol Cell Endocrinol 221:57–66. https://doi.org/10.1016/j.mce.2004.03.012
Sengupta M, Deb I, Sharma GD et al (2013) Human sperm and other seminal constituents in male infertile patients from arsenic and cadmium rich areas of southern Assam. Syst Biol Reprod Med 59:199–209. https://doi.org/10.3109/19396368.2013.783143
Shank KE, Vetter RJ, Ziemer PL (1977) Uptake and distribution of cadmium in mice following repeated administrations. Arch Environ Contam Toxicol 6:63–68. https://doi.org/10.1007/BF02097750
Sharma RP, Kjellstrom T, McKenzie JM (1983) Cadmium in blood and urine among smokers and non-smokers with high cadmium intake via food. Toxicology 29:163–171. https://doi.org/10.1016/0300-483x(83)90048-3
Shi X, Fu L (2019) Piceatannol inhibits oxidative stress through modification of Nrf2-signaling pathway in testes and attenuates spermatogenesis and steroidogenesis in rats exposed to cadmium during adulthood. Drug Des Devel Ther 13:2811–2824. https://doi.org/10.2147/DDDT.S198444
Shi TY, Chen G, Huang X et al (2012) Effects of reactive oxygen species from activated leucocytes on human sperm motility, viability and morphology. Andrologia 44(Suppl 1):696–703. https://doi.org/10.1111/j.1439-0272.2011.01252.x
Smith SW (2013) The role of chelation in the treatment of other metal poisonings. J Med Toxicol 9:355–369. https://doi.org/10.1007/s13181-013-0343-6
Smith LB, Walker WH (2014) The regulation of spermatogenesis by androgens. Semin Cell Dev Biol 30:2–13. https://doi.org/10.1016/j.semcdb.2014.02.012
Sukhn C, Awwad J, Ghantous A et al (2018) Associations of semen quality with non-essential heavy metals in blood and seminal fluid: data from the environment and male infertility (EMI) study in Lebanon. J Assist Reprod Genet 35:1691–1701. https://doi.org/10.1007/s10815-018-1236-z
Taha EA, Sayed SK, Ghandour NM et al (2013) Correlation between seminal lead and cadmium and seminal parameters in idiopathic oligoasthenozoospermic males. Cent European J Urol 66:84–92. https://doi.org/10.5173/ceju.2013.01.art28
Taylor CM, Golding J, Emond AM (2016) Moderate prenatal cadmium exposure and adverse birth outcomes: a role for sex-specific differences? Paediatr Perinat Epidemiol 30:603–611. https://doi.org/10.1111/ppe.12318
Taylor CM, Emond AM, Lingam R et al (2018) Prenatal lead, cadmium and mercury exposure and associations with motor skills at age 7years in a UK observational birth cohort. Environ Int 117:40–47. https://doi.org/10.1016/j.envint.2018.04.032
Thijssen S, Maringwa J, Faes C et al (2007) Chronic exposure of mice to environmentally relevant, low doses of cadmium leads to early renal damage, not predicted by blood or urine cadmium levels. Toxicology 229:145–156. https://doi.org/10.1016/j.tox.2006.10.011
Tung NT, Cuong TD, Hung TM et al (2013) Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum. Bioorg Med Chem Lett 23:1428–1432. https://doi.org/10.1016/j.bmcl.2012.12.066
Ujah GA, Nna VU, Agah MI et al (2018) Effect of quercetin on cadmium chloride-induced impairments in sexual behaviour and steroidogenesis in male Wistar rats. Andrologia 50. https://doi.org/10.1111/and.12866
Vidal AC, Semenova V, Darrah T et al (2015) Maternal cadmium, iron and zinc levels, DNA methylation and birth weight. BMC Pharmacol Toxicol 16:20. https://doi.org/10.1186/s40360-015-0020-2
Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120. https://doi.org/10.1016/j.mrfmmm.2003.07.011
Wang X, Tian J (2004) Health risks related to residential exposure to cadmium in Zhenhe County, China. Arch Environ Health 59:324–330. https://doi.org/10.3200/AEOH.59.6.324-330
Wang H, Liu L, Hu YF et al (2016a) Maternal serum cadmium level during pregnancy and its association with small for gestational age infants: a population-based birth cohort study. Sci Rep 6:22631. https://doi.org/10.1038/srep22631
Wang L, Li Y, Fu J et al (2016b) Cadmium inhibits mouse sperm motility through inducing tyrosine phosphorylation in a specific subset of proteins. Reprod Toxicol 63:96–106. https://doi.org/10.1016/j.reprotox.2016.05.018
Wang YX, Sun Y, Feng W et al (2016c) Association of urinary metal levels with human semen quality: a cross-sectional study in China. Environ Int 91:51–59. https://doi.org/10.1016/j.envint.2016.02.019
Wang HF, Chang M, Peng TT et al (2017) Exposure to cadmium impairs sperm functions by reducing CatSper in mice. Cell Physiol Biochem 42:44–54. https://doi.org/10.1159/000477113
Wang H, Zhang L, Abel GM et al (2018) Cadmium exposure impairs cognition and olfactory memory in male C57BL/6 mice. Toxicol Sci 161:87–102. https://doi.org/10.1093/toxsci/kfx202
Wang H, Zhang R, Song Y et al (2019a) Protective effect of ganoderma triterpenoids on cadmium-induced testicular toxicity in chickens. Biol Trace Elem Res 187:281–290. https://doi.org/10.1007/s12011-018-1364-4
Wang S, Ren X, Hu X et al (2019b) Cadmium-induced apoptosis through reactive oxygen species-mediated mitochondrial oxidative stress and the JNK signaling pathway in TM3 cells, a model of mouse Leydig cells. Toxicol Appl Pharmacol 368:37–48. https://doi.org/10.1016/j.taap.2019.02.012
Wijesekara GU, Fernando DM, Wijerathna S et al (2015) Environmental and occupational exposures as a cause of male infertility. Ceylon Med J 60:52–56. https://doi.org/10.4038/cmj.v60i2.7090
Wilder LC, Metcalf SW, Orloff KG et al (2001) ASTDR and the trinity industry case study. Agency for Toxic Substances and Disease Registry. AIHAJ 62:557
Wu HM, Lin-Tan DT, Wang ML et al (2008) Cadmium level in seminal plasma may affect the pregnancy rate for patients undergoing infertility evaluation and treatment. Reprod Toxicol 25:481–484. https://doi.org/10.1016/j.reprotox.2008.04.005
Wu X, Guo X, Wang H et al (2017) A brief exposure to cadmium impairs Leydig cell regeneration in the adult rat testis. Sci Rep 7:6337. https://doi.org/10.1038/s41598-017-06870-0
Xiao X, Cheng CY, Mruk DD (2013) Intercellular adhesion molecule-2 is involved in apical ectoplasmic specialization dynamics during spermatogenesis in the rat. J Endocrinol 216:73–86. https://doi.org/10.1530/JOE-12-0434
Xu B, Chia SE, Tsakok M et al (1993) Trace elements in blood and seminal plasma and their relationship to sperm quality. Reprod Toxicol 7:613–618. https://doi.org/10.1016/0890-6238(93)90038-9
Yadav N, Khandelwal S (2008) Effect of Picroliv on cadmium induced testicular damage in rat. Food Chem Toxicol 46:494–501. https://doi.org/10.1016/j.fct.2007.08.035
Yang JM, Arnush M, Chen QY et al (2003) Cadmium-induced damage to primary cultures of rat Leydig cells. Reprod Toxicol 17:553–560. https://doi.org/10.1016/s0890-6238(03)00100-x
Yang Q, Li P, Wen Y et al (2018a) Cadmium inhibits lysine acetylation and succinylation inducing testicular injury of mouse during development. Toxicol Lett 291:112–120. https://doi.org/10.1016/j.toxlet.2018.04.005
Yang SH, Yu LH, Li L et al (2018b) Protective mechanism of sulforaphane on cadmium-induced Sertoli cell injury in mice testis via Nrf2/ARE signaling pathway. Molecules 23. https://doi.org/10.3390/molecules23071774
Yang SH, He JB, Yu LH et al (2019) Protective role of curcumin in cadmium-induced testicular injury in mice by attenuating oxidative stress via Nrf2/ARE pathway. Environ Sci Pollut Res Int 26:34575–34583. https://doi.org/10.1007/s11356-019-06587-9
Zeng X, Lin T, Zhou Y et al (2002) Alterations of serum hormone levels in male workers occupationally exposed to cadmium. J Toxicol Environ Health A 65:513–521. https://doi.org/10.1080/15287390252807975
Zeng X, Jin T, Buchet JP et al (2004a) Impact of cadmium exposure on male sex hormones: a population-based study in China. Environ Res 96:338–344. https://doi.org/10.1016/j.envres.2004.02.004
Zeng X, Jin T, Jiang X et al (2004b) Effects on the prostate of environmental cadmium exposure--a cross-sectional population study in China. Biometals 17:559–565. https://doi.org/10.1023/b:biom.0000045739.89653.67
Zeng Q, Zhou B, Feng W et al (2013) Associations of urinary metal concentrations and circulating testosterone in Chinese men. Reprod Toxicol 41:109–114. https://doi.org/10.1016/j.reprotox.2013.06.062
Zeng Q, Feng W, Zhou B et al (2015) Urinary metal concentrations in relation to semen quality: a cross-sectional study in China. Environ Sci Technol 49:5052–5059. https://doi.org/10.1021/es5053478
Zhang Y, Xu X, Chen A et al (2018) Maternal urinary cadmium levels during pregnancy associated with risk of sex-dependent birth outcomes from an e-waste pollution site in China. Reprod Toxicol 75:49–55. https://doi.org/10.1016/j.reprotox.2017.11.003
Zhou T, Jia X, Chapin RE et al (2004) Cadmium at a non-toxic dose alters gene expression in mouse testes. Toxicol Lett 154:191–200. https://doi.org/10.1016/j.toxlet.2004.07.015
Zhou T, Wang H, Zhang S et al (2016a) S100P is a potential molecular target of cadmium-induced inhibition of human placental trophoblast cell proliferation. Exp Toxicol Pathol 68:565–570. https://doi.org/10.1016/j.etp.2016.09.002
Zhou Y, Fu XM, He DL et al (2016b) Evaluation of urinary metal concentrations and sperm DNA damage in infertile men from an infertility clinic. Environ Toxicol Pharmacol 45:68–73. https://doi.org/10.1016/j.etap.2016.05.020
Zhu H, Li K, Liang J et al (2011) Changes in the levels of DNA methylation in testis and liver of SD rats neonatally exposed to 5-aza-2′-deoxycytidine and cadmium. J Appl Toxicol 31:484–495. https://doi.org/10.1002/jat.1673
Acknowledgments
We would like to thank Editage (www.editage.cn) for English language editing.
Authors’ Contributions
L.J.X., H.L., and B.Z. researched data for the article and wrote the manuscript. L.C. contributed substantially to the discussion of its contents. All authors reviewed and edited the manuscript before submission.
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The authors are grateful to the U.S-China Pediatric Research Exchange Training Program. The personnel expenses for LX and BZ when they worked in the University of Louisville (2018–2021) were in part provided by Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, China, according to this Exchange Program Agreement.
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Xiong, L., Zhou, B., Liu, H., Cai, L. (2021). Comprehensive Review of Cadmium Toxicity Mechanisms in Male Reproduction and Therapeutic Strategies. In: de Voogt, P. (eds) Reviews of Environmental Contamination and Toxicology Volume 258. Reviews of Environmental Contamination and Toxicology, vol 258. Springer, Cham. https://doi.org/10.1007/398_2021_75
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