Abstract
Introduction: Mercury (Hg) is a major environmental contaminant and public health concern, particularly in industrial regions where metallurgical activities contribute to elevated Hg emissions. Genetic factors influencing susceptibility to mercury toxicity remain underexplored in Central Asia. This study investigated genetic predisposition to Hg accumulation and toxicity among residents of Temirtau, Kazakhstan. Methods: A total of 180 residents from Temirtau and 90 control participants were enrolled. Mercury concentrations were measured in blood and hair samples using cold vapor atomic absorption spectrometry. Dietary information was collected to identify major exposure routes. Genotyping for GSTM1, GSTT1, GSTP1 (Ile105Val, rs1695), and GCLM (-588C/T, rs41303970) polymorphisms was performed using PCR and PCR-RFLP methods. Complementary molecular docking analyses were conducted to assess methylmercury (MeHg) interactions with key epigenetic regulators-DNA methyltransferase 1 (DNMT1), histone deacetylases (HDAC1-6), and sirtuin 1 (SIRT1). Results: Individuals carrying GSTM1-null and GCLM variant genotypes exhibited higher Hg accumulation and greater oxidative-stress susceptibility compared with wild-type carriers. Molecular docking revealed moderate binding affinity of MeHg within the catalytic domains of DNMT1 and HDAC isoforms, suggesting interference with DNA methylation and histone-modification processes. Although exposure levels were considerably lower than those in classical Minamata incidents, subclinical effects and genotype-environment interactions were evident. Discussion: These findings highlight oxidative stress and epigenetic dysregulation as potential mechanisms underlying interindividual variability in mercury toxicity. The integration of genetic and molecular-modeling approaches provides valuable insights for risk assessment and preventive strategies in populations chronically exposed to industrial pollutants.