Metallothionein gene polymorphism associated with Cd and Hg levels in non-obstructive azoospermia patients: a hospital-based observational study
DOI:
https://doi.org/10.18203/2320-1770.ijrcog20251966Keywords:
Azoospermia, Hypospermatogenesis, Copy number variants, Heavy metals, Cadmium, Mercury, Male infertilityAbstract
Background: Heavy metals, such as Cadmium (Cd), Arsenic (As), Mercury (Hg) and Lead (Pb) might potentially induce reproductive toxicity in male infertility patients, regardless of the varying concentrations of these heavy metals in the blood. Genetic polymorphism is one of the least studied internal contributing factors in male infertility cases associated with high level of heavy metal in blood. Therefore, this study aims at identifying the difference in the serum levels of heavy metals in non-obstructive azoospermia (NOA) patients associated with genetic variants.
Methods: It’s a hospital based observational study where patients reporting with azoospermia due to hypospermatogenesis (HS) were recruited prospectively. Comprehensive clinical history, and blood samples were collected. Whole exome sequencing (WES) and was performed for 50 HS patients to identify variants. Inductively coupled plasma mass spectrometry (ICP-MS) was performed to assess levels of Cd, As, Hg and Pb levels in serum samples of 50 HS patients. Statistical analysis was performed to determine difference in heavy metal concentration of HS patients with and without the presence of metallothionein gene associated single nucleotide polymorphism (SNP).
Results: Genomic analysis for SNPs identified deleterious candidate variants in MT1A (rs11640851 and rs8052394) associated with 18/50, MT1E (rs138690474) associated with 4/50 and MT4 (rs11643815) associated with 5/50 HS patients. A statistically significant difference in the blood concentration of Cd and Hg was observed in HS patients associated with metallothionein gene SNPs.
Conclusions: This exploratory genomic analysis conducted on HS patients shows prevalence of deleterious candidate SNPs in metallothionein gene. The HS patients with candidate SNPs showed higher levels of Cd and Hg which indicate the genomic susceptibly towards heavy metal-induced reproductive toxicity.
Metrics
References
Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod. Biol. Endocrinol. 2015;13:1-9. DOI: https://doi.org/10.1186/s12958-015-0032-1
Figa-Talamanca I. Traina ME, Urbani E. Occupational exposures to metals, solvents and pesticides: Recent evidence on male reproductive effects and biological markers. Occup Med. 2001;51:174-88. DOI: https://doi.org/10.1093/occmed/51.3.174
Kopp R, Martínez IO, Legradi J, Legler J. Exposure to endocrine disrupting chemicals perturbs lipid metabolism and circadian rhythms. J Environ Sci. 2017;62:133-7. DOI: https://doi.org/10.1016/j.jes.2017.10.013
Balabanic D, Klemencic AK. Diet containing endocrine-disruptors and reproductive health. Handbook of Diet and Nutrition in the Menstrual Cycle. J Reprod Fertil. 2014;2014:359–72. DOI: https://doi.org/10.3920/978-90-8686-767-7_22
Balabaniˇc D, Rupnik MS, Klemenˇciˇc AK. Negative impact of endocrine-disrupting compounds on human reproductive health. Reprod Fertil Dev. 2011;23:403–16. DOI: https://doi.org/10.1071/RD09300
Sekovanić A, Jurasović J, Piasek M. gene polymorphisms in relation to diseases and trace element levels in humans. Archives of Industrial Hygiene and Toxicology. 2020;71(1):27-47. DOI: https://doi.org/10.2478/aiht-2020-71-3349
Kimura T, Kambe T. The functions of metallothionein and ZIP and ZnT transporters: an overview and perspective. Int J Mol Sci. 2016;17:336. DOI: https://doi.org/10.3390/ijms17030336
Pan J, Plant JA, Voulvoulis N, Oates CJ, Ihlenfeld C. Cadmium levels in Europe: implications for human health. Environ. Geochem. Health. 2010;32:1–12. DOI: https://doi.org/10.1007/s10653-009-9273-2
Kayaaltı Z, Aliyev V, Söylemezoğlu T. The potential effect of metallothionein 2A− 5 A/G single nucleotide polymorphism on blood cadmium, lead, zinc and copper levels. Toxicol Applied Pharmacol. 2011;256(1):1-7. DOI: https://doi.org/10.1016/j.taap.2011.06.023
Arrifano GP, Augusto-Oliveira M, Lopes-Araujo A, Santos-Sacramento L, Macchi BM, Nascimento J, et al. Global Human Threat: The Potential Synergism between Mercury Intoxication and COVID-19. Int J Environ Res. Public Health. 2023;20:4207. DOI: https://doi.org/10.3390/ijerph20054207
Arrifano GP, Crespo-Lopez ME, Lopes-Araujo A, Santos-Sacramento L, Barthelemy JL, de Nazare CGL, et al. Neurotoxicity and the Global Worst Pollutants: Astroglial Involvement in Arsenic, Lead, and Mercury Intoxication. Neurochem Res. 2023;48:1047–65. DOI: https://doi.org/10.1007/s11064-022-03725-7
Crespo-Lopez ME, Barthelemy JL, Lopes-Araújo A, Santos-Sacramento L, Leal-Nazaré CG, Soares-Silva I, et al. Revisiting Genetic Influence on Mercury Exposure and Intoxication in Humans: A Scoping Review. Toxics. 2023;11(12):967. DOI: https://doi.org/10.3390/toxics11120967
Agency for Toxic Substances and Disease Registry. ATSDR 2022 Substance Priority List. Available at: https://www.atsdr.cdc.gov/spl/index.html. Accessed on 17 May 2023.
Crespo-Lopez ME, Augusto-Oliveira M, Lopes-Araújo A, Santos-Sacramento L, Souza-Monteiro JR, da Rocha FF, et al. Mercury Neurotoxicity in Gold Miners. In: Lucchini RG, Aschner M, Costa LG, editors. Advances in Neurotoxicology. Cambridge (MA): Academic Press; 2022;7:283–314. DOI: https://doi.org/10.1016/bs.ant.2022.04.003
Machado CLR, Crespo-Lopez ME, Augusto-Oliveira M, Arrifano GP, Macchi BM, Lopes-Araujo A, et al. Eating in the Amazon: Nutritional Status of the Riverine Populations and Possible Nudge Interventions. Foods. 2021;10:1015. DOI: https://doi.org/10.3390/foods10051015
Rodriguez Martin-Doimeadios RC, Berzas Nevado JJ, Guzman Bernardo FJ, Jimenez Moreno M, Arrifano GP, Herculano AM, et al. Comparative Study of Mercury Speciation in Commercial Fishes of the Brazilian Amazon. Environ Sci Pollut Res Int. 2014;21:7466–79. DOI: https://doi.org/10.1007/s11356-014-2680-7
Mocevic E, Specht IO, Marott JL, Giwercman A, Jönsson BA, Toft G, et al. Environmental Mercury Exposure, Semen Quality and Reproductive Hormones in Greenlandic Inuit and European Men: A Cross-Sectional Study. Asian J Androl. 2013;15(1):97. DOI: https://doi.org/10.1038/aja.2012.121
Arabi M, Heydarnejad MS. In vitro mercury exposure on spermatozoa from normospermic individuals. Pak J Biol Sci. 2007;10:2448–53. DOI: https://doi.org/10.3923/pjbs.2007.2448.2453
Boujbiha MA, Hamden K, Guermazi F, Bouslama A, Omezzine A et al. Testicular toxicity in mercuric chloride treated rats: association with oxidative stress. Reprod Toxicol. 2009;28:81–9. DOI: https://doi.org/10.1016/j.reprotox.2009.03.011
Homma-Takeda S, Kugenuma Y, Iwamuro T, Kumagai Y, Shimojo N. Impairment of spermatogenesis in rats by methylmercury: involvement of stage- and cell-specific germ cell apoptosis. Toxicol. 2001;169:25–35. DOI: https://doi.org/10.1016/S0300-483X(01)00487-5
Choy CM, Lam CW, Cheung LT, Briton-Jones CM, Cheung LP et al. Infertility, blood mercury concentrations and dietary seafood consumption: a case–control study. BJOG. 2002;109:1121–5. DOI: https://doi.org/10.1111/j.1471-0528.2002.02084.x
Basta PC, Viana PVDS, Vasconcellos ACSD, Périssé ARS, Hofer CB, Paiva NS, et al. Mercury Exposure in Munduruku Indigenous Communities from Brazilian Amazon: Methodological Background and an Overview of the Principal Results. Int J Environ Res Public Health. 2021;18:9222. DOI: https://doi.org/10.3390/ijerph18179222
Silva MC, de Oliveira RAA, Vasconcellos ACS, Rebouças BH, Pinto BD, Lima MO, et al. Chronic Mercury Exposure and GSTP1 Polymorphism in Munduruku Indigenous from Brazilian Amazon. Toxics. 2023;11:138. DOI: https://doi.org/10.3390/toxics11020138
Andreoli V, Sprovieri F. Genetic aspects of susceptibility to mercury toxicity: An overview. Int J Environ Res Public Health. 2017;14:93. DOI: https://doi.org/10.3390/ijerph14010093
Sharma N, Halder A, Kaushal S, Kumar M, Jain M. Identification of deleterious variants associated with male infertility genes in a cohort of idiopathic hypospermatogenesis patients. Frontiers In Reproductive Health. 2025;6:1494585. DOI: https://doi.org/10.3389/frph.2024.1494585
Kamiński P, Baszyński J, Jerzak I, Kavanagh BP, Nowacka-Chiari E, Polanin M, et al. External and Genetic Conditions Determining Male Infertility. Int J Mol Sci. 2020;21(15):5274. DOI: https://doi.org/10.3390/ijms21155274
Machado-Neves M. Effect of heavy metals on epididymal morphology and function: An integrative review. Chemosphere. 2022;291:133020. DOI: https://doi.org/10.1016/j.chemosphere.2021.133020
Hassan J, Elmetwalli A, Helal M, Al Munajer EA, Hussien TM, Saad AAA, et al. Cadmium Exposure and Its Association with Oxidative Stress, MT1A Methylation, and Idiopathic Male Infertility in Egypt: A Case-Control Study. Food Chem Toxicol. 2024;192:114925. DOI: https://doi.org/10.1016/j.fct.2024.114925
Perini JA, Cardoso JV, Knesse ADO, Pessoa-Silva FO, Vasconcellos ACSD, Machado DE, et al. Single-Nucleotide Polymorphisms Associated with Mercury Levels and Neurological Symptoms: An Overview. Toxics. 2024;12(3):226. DOI: https://doi.org/10.3390/toxics12030226
Yang L, Li H, Yu T, Zhao H, Cherian MG, Cai L, et al. Polymorphisms in Metallothionein-1 and -2 Genes Associated with the Risk of Type 2 Diabetes Mellitus and Its Complications. Am J Physiol Endocrinol Metab. 2008;294(5):E987–92. DOI: https://doi.org/10.1152/ajpendo.90234.2008
Yang CC, Lin CI, Lee SS, Wang CL, Dai CY, Chuang HY. The Association of Blood Lead Levels and Renal Effects May Be Modified by Genetic Combinations of Metallothionein 1A 2A Polymorphisms. Sci Rep. 2020;10(1):9603. DOI: https://doi.org/10.1038/s41598-020-66645-y
Downloads
Published
How to Cite
Issue
Section
