vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-50vavilov-5115Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSТоксичные металлы и генетический полиморфизм у коренного населения Севера Азии и АмерикиToxic metals and genetic polymorphism in indigenous populations of northern Asia and AmericaМалярчукБ. А.MalyarchukB. A.

Магадан

Magadan

malbor@mail.ruПохилюкН. В.PokhilyukN. V.

Магадан

Magadan

Институт биологических проблем Севера Дальневосточного отделения Российской академии наукРоссияInstitute of Biological Problems of the North of the Far Eastern Branch of the Russian Academy of SciencesRussian Federation202626052026303461469Copyright © Малярчук Б.А., Похилюк Н.В., 20262026Малярчук Б.А., Похилюк Н.В.Malyarchuk B.A., Pokhilyuk N.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5115

В настоящей работе у коренного населения Сибири проанализирован полиморфизм генов, кодирующих ферменты метаболизма тяжелых металлов, на основе данных о содержании ртути, свинца и кадмия в крови у канадских эскимосов – носителей различных генотипов; изучен также полиморфизм генетических локусов, связанных с чувствительностью к воздействию мышьяка по данным о содержании неорганического мышьяка в моче у коренного населения Анд, длительное время (в течение тысячелетий) потребляющего питьевую воду с повышенным содержанием мышьяка. Для поиска генетических маркеров воздействия токсичных металлов на организм человека использован популяционно-генетический подход, направленный на анализ генетических различий между популяциями, проживающими в разных условиях природной среды (и в разных условиях загрязнения токсичными элементами). Статистически значимые различия главным образом обнаружены между коренным населением Северо-Восточной Сибири (эскимосы, чукчи и коряки) и выборками из центральной (эвены, эвенки, якуты) и южной (алтайцы, шорцы, буряты) частей Сибири. Максимальные значения статистики PBS (population branch statistics), свидетельствующие о вероятном действии отбора на генетические локусы чувствительности к воздействию ртути, выявлены в семи локусах генов MTHFR (rs2274976 и rs1801131), GPX4 (rs713041), ABCB1 (rs1128503), AHR (rs2066853), TXNRD2 (rs5748469) иSEPHS2 (rs1133238). К генетическим маркерам воздействия свинца могут быть отнесены локусы rs713041 (GPX4), rs7483 (GSTM3) и rs2282143 (SLC22A1). В отношении распределения кадмия в крови информативны локусы rs2274976 (MTHFR) и rs1056836 (CYP1B1). Обнаружено, что в популяциях коренного населения Северо-Востока Сибири с высокой частотой (65.8 %) распространены варианты полиморфизма гена AS3MT, защищающие от воздействия неорганического мышьяка, хотя сведения о долговременном употреблении коренными жителями побережий Чукотки и Приохотья питьевой воды, загрязненной мышьяком, отсутствуют. Предполагается, что вероятным источником мышьяка, а также других токсичных элементов на Северо-Востоке Сибири могут быть морепродукты, являющиеся основой традиционной «арктической» диеты коренного населения прибрежных районов северных морей. Для прояснения механизмов долговременного воздействия токсичных металлов на генетическую структуру популяций коренного населения Крайнего Севера необходимы дальнейшие молекулярно-генетические, биохимические и токсикологические исследования.

The polymorphism of genes encoding enzymes involved in heavy metal metabolism was analyzed in indigenous Siberian populations based on the mercury, lead, and cadmium contents in the blood of Canadian Inuit carrying different genotypes. Additionally, we examined the polymorphism of genetic loci associated with sensitivity to arsenic exposure in indigenous Siberian populations using data on inorganic arsenic content in the urine of indigenous Andean populations who had consumed drinking water with elevated arsenic levels for thousands of years. A population genetic approach was used to seek genetic markers of toxic metal exposure in humans by analyzing genetic differences between populations living in different natural environments and under different conditions of toxic element contamination. Statistically significant differences were primarily observed between indigenous populations in Northeast Siberia (Siberian Eskimo (Yupik), Chukchi, and Koryaks) and samples from the central (Evens, Evenki, and Yakuts) and southern (Altaians, Shors, and Buryats) regions of Siberia. The maximum population branch statistics (PBS) values, which indicate the probable effect of selection on genetic loci sensitive to mercury exposure, were identified in seven gene loci: MTHFR (rs2274976 and rs1801131), GPX4 (rs713041), ABCB1 (rs1128503), AHR (rs2066853), TXNRD2 (rs5748469), and SEPHS2 (rs1133238). Loci rs713041 (GPX4), rs7483 (GSTM3), and rs2282143 (SLC22A1) can be considered genetic markers of lead exposure. Loci rs2274976 (MTHFR) and rs1056836 (CYP1B1) provide information about cadmium distribution in blood. It was found that protective variants of the AS3MT gene polymorphism are widespread (65.8 %) in the indigenous populations of Northeast Siberia. This is despite the lack of information regarding the long-term consumption of arsenic-contaminated drinking water by indigenous peoples along the Chukotka and Priokhotye coasts. It is hypothesized that seafood, which constitutes the core of the traditional “Arctic” diet of the indigenous populations inhabiting the coastal regions of the northern seas, may potentially be a significant source of arsenic and other toxic elements in Northeast Siberia. Further molecular, biochemical, and toxicological studies are necessary to elucidate the mechanisms by which toxic metals impact the genetic structure of indigenous populations in the Far North over long periods of time.

генетические маркерыгенетическая дифференциацияпопуляции человекаСибирьртутьсвинецкадмиймышьякgenetic markersgenetic differentiationhuman populationsSiberiamercuryleadcadmiumarsenicReferencesAdlard B., Bonefeld-Jørgensen E.C., Dudarev A.A., Olafsdottir K., Abass K., Ayotte P., Caron-Beaudoin É., … Ratelle M., Rautio A., Timmerman A., Weihe P., Wennberg M. Levels and trends of metals in human populations living in the Arctic. Int J Circumpolar Health. 2024;83(1):2386140. doi 10.1080/22423982.2024.2386140Adlard B., Bonefeld-Jørgensen E.C., Dudarev A.A., Olafsdottir K., Abass K., Ayotte P., Caron-Beaudoin É., … Ratelle M., Rautio A., Timmerman A., Weihe P., Wennberg M. Levels and trends of metals in human populations living in the Arctic. Int J Circumpolar Health. 2024;83(1):2386140. doi 10.1080/22423982.2024.2386140Alqahtani M.A., El-Ghiaty M.A., El-Mahrouk S.R., El-Kadi A.O.S. Differential modulatory effects of methylmercury (MeHg) on Ahrregulated genes in extrahepatic tissues of C57BL/6 mice. Biol Trace Elem Res. 2024;202(11):5071-5080. doi 10.1007/s12011-023-04050-yAlqahtani M.A., El-Ghiaty M.A., El-Mahrouk S.R., El-Kadi A.O.S. Differential modulatory effects of methylmercury (MeHg) on Ahrregulated genes in extrahepatic tissues of C57BL/6 mice. Biol Trace Elem Res. 2024;202(11):5071-5080. doi 10.1007/s12011-023-04050-yApata M., Arriaza B., Llop E., Moraga M. Human adaptation to arsenic in Andean populations of the Atacama Desert. Am J Phys Anthropol. 2017;163(1):192-199. doi 10.1002/ajpa.23193Apata M., Arriaza B., Llop E., Moraga M. Human adaptation to arsenic in Andean populations of the Atacama Desert. Am J Phys Anthropol. 2017;163(1):192-199. doi 10.1002/ajpa.23193Arefieva A.S., Barigina V.V., Zatsepina O.V. The present-day ideas about impact of mercuric compounds at cell and system levels (review). Ekologiya Cheloveka = Human Ecology. 2010;8:35-41 (in Russian)Arefieva A.S., Barigina V.V., Zatsepina O.V. The present-day ideas about impact of mercuric compounds at cell and system levels (review). Ekologiya Cheloveka = Human Ecology. 2010;8:35-41 (in Russian)Ayotte P., Carrier A., Ouellet N., Boiteau V., Abdous B., Sidi E.A., Château-Degat M.L., Dewailly É. Relation between methylmercury exposure and plasma paraoxonase activity in inuit adults from Nunavik. Environ Health Perspect. 2011;119(8):1077-1083. doi 10.1289/ehp.1003296Ayotte P., Carrier A., Ouellet N., Boiteau V., Abdous B., Sidi E.A., Château-Degat M.L., Dewailly É. Relation between methylmercury exposure and plasma paraoxonase activity in inuit adults from Nunavik. Environ Health Perspect. 2011;119(8):1077-1083. doi 10.1289/ehp.1003296Bagryantseva O.V., Khotimchenko S.A. Risks associated with the consumption of inorganic and organic arsenic. Voprosy Pitaniya = Problems of Nutrition. 2021;90(6):6-17. doi 10.33029/0042-8833-2021-90-6-6-17 (in Russian)Bagryantseva O.V., Khotimchenko S.A. Risks associated with the consumption of inorganic and organic arsenic. Voprosy Pitaniya = Problems of Nutrition. 2021;90(6):6-17. doi 10.33029/0042-8833-2021-90-6-6-17 (in Russian)Basu N., Abass K., Dietzd R., Krümmel E., Rautio A., Weihe P. The impact of mercury contamination on human health in the Arctic: a state of the science review. Sci Total Environ. 2022;831:154793. doi 10.1016/j.scitotenv.2022.154793Basu N., Abass K., Dietzd R., Krümmel E., Rautio A., Weihe P. The impact of mercury contamination on human health in the Arctic: a state of the science review. Sci Total Environ. 2022;831:154793. doi 10.1016/j.scitotenv.2022.154793Becker P.R. Concentration of chlorinated hydrocarbons and heavy metals in Alaska Arctic marine mammals. Mar Pollut Bull. 2000; 40(10):819-829. doi 10.1016/S0025-326X(00)00076-XBecker P.R. Concentration of chlorinated hydrocarbons and heavy metals in Alaska Arctic marine mammals. Mar Pollut Bull. 2000; 40(10):819-829. doi 10.1016/S0025-326X(00)00076-XCardona A., Pagani L., Antao T., Lawson D.J., Eichstaedt C.A., Yngvadottir B., Shwe M.T., … Willerslev E., Tyler-Smith C., Malyarchuk B.A., Derenko M.V., Kivisild T. Genome-wide analysis of cold adaptation in indigenous Siberian populations. PloS One. 2014;9(5):e98076. doi 10.1371/journal.pone.0098076Cardona A., Pagani L., Antao T., Lawson D.J., Eichstaedt C.A., Yngvadottir B., Shwe M.T., … Willerslev E., Tyler-Smith C., Malyarchuk B.A., Derenko M.V., Kivisild T. Genome-wide analysis of cold adaptation in indigenous Siberian populations. PloS One. 2014;9(5):e98076. doi 10.1371/journal.pone.0098076Chen W., Zhang X., Zhang W., Peng C., Zhu W., Chen X. Polymorphisms of SLCO1B1 rs4149056and SLC22A1 rs2282143 are associated with responsiveness to acitretin in psoriasis patients. Sci Rep. 2018;8:13182. doi 10.1038/s41598-018-31352-2Chen W., Zhang X., Zhang W., Peng C., Zhu W., Chen X. Polymorphisms of SLCO1B1 rs4149056and SLC22A1 rs2282143 are associated with responsiveness to acitretin in psoriasis patients. Sci Rep. 2018;8:13182. doi 10.1038/s41598-018-31352-2Crespo-Lopez M.E., Barthelemy J.L., Lopes-Araújo A., Santos-Sacramento L., Leal-Nazaré C.G., Soares-Silva I., Macchi B.M., do Nascimento J.L.M., Arrifano G.P., Augusto-Oliveira M. Revisiting genetic influence on mercury exposure and intoxication in humans: a scoping review. Toxics. 2023;11(12):967. doi 10.3390/toxics11120967Crespo-Lopez M.E., Barthelemy J.L., Lopes-Araújo A., Santos-Sacramento L., Leal-Nazaré C.G., Soares-Silva I., Macchi B.M., do Nascimento J.L.M., Arrifano G.P., Augusto-Oliveira M. Revisiting genetic influence on mercury exposure and intoxication in humans: a scoping review. Toxics. 2023;11(12):967. doi 10.3390/toxics11120967De Loma J., Vicente M., Tirado N., Ascui F., Vahter M., Gardon J., Schlebusch C.M., Broberg K. Human adaptation to arsenic in Bolivians living in the Andes. Chemosphere. 2022;301:134764. doi 10.1016/j.chemosphere.2022.134764De Loma J., Vicente M., Tirado N., Ascui F., Vahter M., Gardon J., Schlebusch C.M., Broberg K. Human adaptation to arsenic in Bolivians living in the Andes. Chemosphere. 2022;301:134764. doi 10.1016/j.chemosphere.2022.134764Đukić-Ćosić D., Baralić K., Javorac D., Buha Djordjevic A., Bulat Z. An overview of molecular mechanisms in cadmium toxicity. Curr Opin Toxicol. 2020;19:56-62. doi 10.1016/j.cotox.2019.12.002Đukić-Ćosić D., Baralić K., Javorac D., Buha Djordjevic A., Bulat Z. An overview of molecular mechanisms in cadmium toxicity. Curr Opin Toxicol. 2020;19:56-62. doi 10.1016/j.cotox.2019.12.002Eichstaedt C., Antao T., Cardona A., Pagani L., Kivisild T., Mormina M. Positive selection of AS3MT to arsenic water in Andean populations. Mutat Res. 2015;780:97-102. doi 10.1016/j.mrfmmm.2015.07.007Eichstaedt C., Antao T., Cardona A., Pagani L., Kivisild T., Mormina M. Positive selection of AS3MT to arsenic water in Andean populations. Mutat Res. 2015;780:97-102. doi 10.1016/j.mrfmmm.2015.07.007Engström K., Vahter M., Mlakar S.J., Concha G., Nermell B., Raqib R., Cardozo A., Broberg K. Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism. Environ Health Perspect. 2011;119: 182-188. doi 10.1289/ehp.1002471Engström K., Vahter M., Mlakar S.J., Concha G., Nermell B., Raqib R., Cardozo A., Broberg K. Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism. Environ Health Perspect. 2011;119: 182-188. doi 10.1289/ehp.1002471Excoffier L., Lischer H.E. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10(3):564-567. doi 10.1111/j.1755-0998.2010.02847.xExcoffier L., Lischer H.E. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10(3):564-567. doi 10.1111/j.1755-0998.2010.02847.xFernandez-Llamazares A., Garteizgogeascoa M., Basu N., Brondizio E.S., Cabeza M., Martínez-Alier J., McElwee P., Reyes-García V. A state-of-the-art review of indigenous peoples and environmental pollution. Integr Environ Assess Manag. 2020;16(3):324-341. doi 10.1002/ieam.4239Fernandez-Llamazares A., Garteizgogeascoa M., Basu N., Brondizio E.S., Cabeza M., Martínez-Alier J., McElwee P., Reyes-García V. A state-of-the-art review of indigenous peoples and environmental pollution. Integr Environ Assess Manag. 2020;16(3):324-341. doi 10.1002/ieam.4239Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G., Boers G.J., den Heijer M., Kluijtmans L.A., van den Heuvel L.P. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-113. doi 10.1038/ng0595-111Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G., Boers G.J., den Heijer M., Kluijtmans L.A., van den Heuvel L.P. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-113. doi 10.1038/ng0595-111Gamov M.K., Ivanova A.E., Mironova E.K., Tsygankov V.Yu. Heavy metals and arsenic in commercial fish of the Sea of Japan, Sea of Okhotsk, and Bering Sea: current status (literature review). Morskoy Biologicheskii Zhurnal = Marine Biological Journal. 2022;7(4): 14-30. doi 10.21072/mbj.2022.07.4.02 (in Russian)Gamov M.K., Ivanova A.E., Mironova E.K., Tsygankov V.Yu. Heavy metals and arsenic in commercial fish of the Sea of Japan, Sea of Okhotsk, and Bering Sea: current status (literature review). Morskoy Biologicheskii Zhurnal = Marine Biological Journal. 2022;7(4): 14-30. doi 10.21072/mbj.2022.07.4.02 (in Russian)Gautrey H., Nicol F., Sneddon A.A., Hall J., Hesketh J. A T/C polymorphism in the GPX4 3′UTR affects the selenoprotein expression pattern and cell viability in transfected Caco-2 cells. Biochim Biophys Acta. 2011;1810(6):584-591. doi 10.1016/j.bbagen.2011.03.016Gautrey H., Nicol F., Sneddon A.A., Hall J., Hesketh J. A T/C polymorphism in the GPX4 3′UTR affects the selenoprotein expression pattern and cell viability in transfected Caco-2 cells. Biochim Biophys Acta. 2011;1810(6):584-591. doi 10.1016/j.bbagen.2011.03.016Ghisari M., Long M., Bonefeld-Jørgensen E.C. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans. Int J Circumpolar Health. 2013;72:21113. doi 10.3402/ijch.v72i0.21113Ghisari M., Long M., Bonefeld-Jørgensen E.C. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans. Int J Circumpolar Health. 2013;72:21113. doi 10.3402/ijch.v72i0.21113González-Martínez F., Johnson-Restrepo B., Quiñones L.A. Arsenic inorganic exposure, metabolism, genetic biomarkers and its impact on human health: a mini-review. Toxicol Lett. 2024;398:105-117. doi 10.1016/j.toxlet.2024.06.008González-Martínez F., Johnson-Restrepo B., Quiñones L.A. Arsenic inorganic exposure, metabolism, genetic biomarkers and its impact on human health: a mini-review. Toxicol Lett. 2024;398:105-117. doi 10.1016/j.toxlet.2024.06.008Gonzalez-Villalva A., Marcela R.L., Nelly L.V., Patricia B.N., Guadalupe M.R., Brenda C.T., Maria Eugenia C.V., Martha U.C., Isabel G.P., Fortoul T.I. Lead systemic toxicity: a persistent problem for health. Toxicology. 2025;515:154163. doi 10.1016/j.tox.2025.154163Gonzalez-Villalva A., Marcela R.L., Nelly L.V., Patricia B.N., Guadalupe M.R., Brenda C.T., Maria Eugenia C.V., Martha U.C., Isabel G.P., Fortoul T.I. Lead systemic toxicity: a persistent problem for health. Toxicology. 2025;515:154163. doi 10.1016/j.tox.2025.154163Jorge A.O.S., Chamorro F., Carpena M., Echave J., Pereira A.G., Oliveira M.B.P.P., Prieto M.A. Protection of selenium against methylmercury in the human body: a comprehensive review of biomolecular interactions. Biol Life Sci Forum. 2024;35(1):8. doi 10.3390/blsf2024035008Jorge A.O.S., Chamorro F., Carpena M., Echave J., Pereira A.G., Oliveira M.B.P.P., Prieto M.A. Protection of selenium against methylmercury in the human body: a comprehensive review of biomolecular interactions. Biol Life Sci Forum. 2024;35(1):8. doi 10.3390/blsf2024035008Melo S.S., Persuhn D.C., Meirelles M.S., Jordao A.A., Vannucchi H. G1793A polymorphisms in the methylenetetrahydrofolate gene: effect of folic acid on homocysteine levels. Mol Nutr Food Res. 2006; 50(8):769-774. doi 10.1002/mnfr.200600020Melo S.S., Persuhn D.C., Meirelles M.S., Jordao A.A., Vannucchi H. G1793A polymorphisms in the methylenetetrahydrofolate gene: effect of folic acid on homocysteine levels. Mol Nutr Food Res. 2006; 50(8):769-774. doi 10.1002/mnfr.200600020Mohammadi-Bardbori A., Vikstrom Bergander L., Rannug U., Rannug A. NADPH oxidase-dependent mechanism explains how arsenic and other oxidants can activate aryl hydrocarbon receptor signaling. Chem Res Toxicol. 2015;28(12):2278-2286. doi 10.1021/acs.chemrestox.5b00415Mohammadi-Bardbori A., Vikstrom Bergander L., Rannug U., Rannug A. NADPH oxidase-dependent mechanism explains how arsenic and other oxidants can activate aryl hydrocarbon receptor signaling. Chem Res Toxicol. 2015;28(12):2278-2286. doi 10.1021/acs.chemrestox.5b00415Parajuli R.P., Goodrich J.M., Chan L.H.M., Ayotte P., Lemire M., Hegele R.A., Basu N. Genetic polymorphisms are associated with exposure biomarkers for metals and persistent organic pollutants among Inuit from the inuvialuit settlement region, Canada. Sci Total Environ. 2018;634:569-578.Parajuli R.P., Goodrich J.M., Chan L.H.M., Ayotte P., Lemire M., Hegele R.A., Basu N. Genetic polymorphisms are associated with exposure biomarkers for metals and persistent organic pollutants among Inuit from the inuvialuit settlement region, Canada. Sci Total Environ. 2018;634:569-578.Parajuli R.P., Goodrich J.M., Chan H.M., Lemire M., Ayotte P., Hegele R.A., Basu N. Variation in biomarker levels of metals, persistent organic pollutants, and omega-3 fatty acids in association with genetic polymorphisms among Inuit in Nunavik, Canada. Environ Res. 2021;200:111393. doi 10.1016/j.envres.2021.111393Parajuli R.P., Goodrich J.M., Chan H.M., Lemire M., Ayotte P., Hegele R.A., Basu N. Variation in biomarker levels of metals, persistent organic pollutants, and omega-3 fatty acids in association with genetic polymorphisms among Inuit in Nunavik, Canada. Environ Res. 2021;200:111393. doi 10.1016/j.envres.2021.111393Perini J.A., Cardoso J.V., Knesse A.O., Pessoa-Silva F.O., Vasconcellos A.C.S., Machado D.E., Basta P.C. Single-nucleotide polymorphisms associated with mercury levels and neurological symptoms: an overview. Toxics. 2024;12(3):226. doi 10.3390/toxics12030226Perini J.A., Cardoso J.V., Knesse A.O., Pessoa-Silva F.O., Vasconcellos A.C.S., Machado D.E., Basta P.C. Single-nucleotide polymorphisms associated with mercury levels and neurological symptoms: an overview. Toxics. 2024;12(3):226. doi 10.3390/toxics12030226Qu F., Zheng W. Cadmium exposure: mechanisms and pathways of toxicity and implications for human health. Toxics. 2024;12:388. doi 10.3390/toxics12060388Qu F., Zheng W. Cadmium exposure: mechanisms and pathways of toxicity and implications for human health. Toxics. 2024;12:388. doi 10.3390/toxics12060388Sánchez Rodríguez L.H., Medina Pérez O.M., Rondón González F., Rincón Cruz G., Rocha Muñoz L., Flórez-Vargas O. Genetic polymorphisms in multispecific transporters mitigate mercury nephrotoxicity in an artisanal and small-scale gold mining community in Colombia. Toxicol Sci. 2020;178(2):338-346. doi 10.1093/toxsci/kfaa142Sánchez Rodríguez L.H., Medina Pérez O.M., Rondón González F., Rincón Cruz G., Rocha Muñoz L., Flórez-Vargas O. Genetic polymorphisms in multispecific transporters mitigate mercury nephrotoxicity in an artisanal and small-scale gold mining community in Colombia. Toxicol Sci. 2020;178(2):338-346. doi 10.1093/toxsci/kfaa142Schläwicke Engström K., Nermell B., Concha G., Strömberg U., Vahter M., Broberg K. Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res. 2009;667(1-2):4-14. doi 10.1016/j.mrfmmm.2008.07.003Schläwicke Engström K., Nermell B., Concha G., Strömberg U., Vahter M., Broberg K. Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res. 2009;667(1-2):4-14. doi 10.1016/j.mrfmmm.2008.07.003Schlebusch C.M., Gattepaille L.M., Engström K., Vahter M., Jakobsson M., Broberg K. Human adaptation to arsenic-rich environments. Mol Biol Evol. 2015;32(6):1544-1555. doi 10.1093/molbev/msv046Schlebusch C.M., Gattepaille L.M., Engström K., Vahter M., Jakobsson M., Broberg K. Human adaptation to arsenic-rich environments. Mol Biol Evol. 2015;32(6):1544-1555. doi 10.1093/molbev/msv046Stajnko A., Palir N., Snoj Tratnik J., Mazej D., Sešek Briški A., Runkel A.A., Horvat M., Falnoga I. Genetic susceptibility to low-level lead exposure in men: insights from ALAD polymorphisms. Int J Hyg Environ Health. 2024;256:114315. doi 10.1016/j.ijheh.2023.114315Stajnko A., Palir N., Snoj Tratnik J., Mazej D., Sešek Briški A., Runkel A.A., Horvat M., Falnoga I. Genetic susceptibility to low-level lead exposure in men: insights from ALAD polymorphisms. Int J Hyg Environ Health. 2024;256:114315. doi 10.1016/j.ijheh.2023.114315Tetlow N., Robinson A., Mantle T., Board P. Polymorphism of human mu class glutathione transferases. Pharmacogenetics. 2004;14(6): 359-368. doi 10.1097/00008571-200406000-00005Tetlow N., Robinson A., Mantle T., Board P. Polymorphism of human mu class glutathione transferases. Pharmacogenetics. 2004;14(6): 359-368. doi 10.1097/00008571-200406000-00005Trifonova E.A., Eremina E.P., Urnov F.D., Stepanov V.A. The genetic diversity and structure of linkage disequilibrium of the MTHFR gene in populations of Northern Eurasia. Acta Naturae. 2012;4(1):53-69Trifonova E.A., Eremina E.P., Urnov F.D., Stepanov V.A. The genetic diversity and structure of linkage disequilibrium of the MTHFR gene in populations of Northern Eurasia. Acta Naturae. 2012;4(1):53-69Wang H., Gan X., Tang Y. Mechanisms of heavy metal cadmium (Cd)- induced malignancy. Biol Trace Elem Res. 2025;203(2):608-623. doi 10.1007/s12011-024-04189-2Wang H., Gan X., Tang Y. Mechanisms of heavy metal cadmium (Cd)- induced malignancy. Biol Trace Elem Res. 2025;203(2):608-623. doi 10.1007/s12011-024-04189-2Warrington N.M., Zhu G., Dy V., Heath A.C., Madden P.A., Hemani G., Kemp J.P., … Montgomery G.W., Martin N.G., Davey Smith G., Evans D.M., Whitfield J.B. Genome-wide association study of blood lead shows multiple associations near ALAD. Hum Mol Genet. 2015;24(13):3871-3879. doi 10.1093/hmg/ddv112Warrington N.M., Zhu G., Dy V., Heath A.C., Madden P.A., Hemani G., Kemp J.P., … Montgomery G.W., Martin N.G., Davey Smith G., Evans D.M., Whitfield J.B. Genome-wide association study of blood lead shows multiple associations near ALAD. Hum Mol Genet. 2015;24(13):3871-3879. doi 10.1093/hmg/ddv112Weisberg I.S., Jacques P.F., Selhub J., Bostom A.G., Chen Z., Curtis Ellison R., Eckfeldt J.H., Rozen R. The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis. 2001;156(2): 409-415. doi 10.1016/s0021-9150(00)00671-7Weisberg I.S., Jacques P.F., Selhub J., Bostom A.G., Chen Z., Curtis Ellison R., Eckfeldt J.H., Rozen R. The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis. 2001;156(2): 409-415. doi 10.1016/s0021-9150(00)00671-7Yi X., Liang Y., Huerta-Sanchez E., Jin X., Cuo Z.X., Pool J.E., Xu X., … Li S., Yang H., Nielsen R., Wang J., Wang J. Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010;329(5987):75-78. doi 10.1126/science.1190371Yi X., Liang Y., Huerta-Sanchez E., Jin X., Cuo Z.X., Pool J.E., Xu X., … Li S., Yang H., Nielsen R., Wang J., Wang J. Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010;329(5987):75-78. doi 10.1126/science.1190371

The authors declare that there are no conflicts of interest present.