The Influence of Genetic Polymorphisms on Mercury Toxicokinetics: Evidence from Epidemiological and In Vitro Studies.

Abstract

Polymorphisms in glutathione pathway and selenoprotein genes are hypothesized to affect Hg accumulation, modify the impact of Hg on blood pressure, and alter enzyme activity of encoded proteins. We utilized a multi-dimensional approach by considering two forms of Hg (methylmercury from fish consumption; elemental Hg from dental amalgams) and 23 polymorphisms in two cohorts- the Michigan Dental Association (MDA, n=511) and Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT, n=353 mothers, 368 children). In the MDA cohort, mean (±SD) urine (1.04±1.18 μg/L) and hair Hg levels (0.49±0.63 μg/g), biomarkers of elemental Hg and methylmercury exposure, respectively, mirrored US population averages, with dentists exhibiting the highest concentrations. While elevated compared to the US population, biomarker Hg levels among ELEMENT mothers (hair) and children (hair, blood, urine) reflected low-level exposures. Simple and multivariate linear regression models investigated the association of polymorphisms with Hg biomarker levels in two cohorts. Statistical modeling in the MDA cohort tested for significant interactions between genotype and exposure sources (fish consumption, dental amalgams) on biomarker (hair, urine) levels. Several polymorphisms were associated with hair Hg (GSTP1: rs1695, rs1138272; GSS: rs3761144; SEPP1: rs7579) and urine Hg (GSTT1 deletion; SEPP1: rs7579). All significant associations (p<0.05) were observed in the MDA cohort, except the rs7579 ‘T’ allele which correlated with lower urine Hg concentrations in both cohorts. We assessed the association of Hg and polymorphisms with systolic and diastolic blood pressure (SBP, DBP) in the MDA cohort. In multivariate models, increasing hair Hg was linked to higher DBP. Contrariwise, urine Hg levels associated with decreasing SBP, a relationship driven by the males. Significant polymorphism-Hg biomarker interactions were not observed in SBP or DBP models. Mechanisms underlying epidemiological associations were explored through in vitro characterization of enzymatic activity and heavy metal inhibition of four GSTP1 variants encoded by two nonsynonymous polymorphisms (rs1695: 105Ile/Val, rs1138272: 114Ala/Val). Kinetic parameters varied significantly (p<0.01) depending on genotype. Allozymes with 105Ile had better catalytic efficiency and greater electrophilic substrate affinity. Inorganic Hg and methylmercury inhibited all GSTP1 variants. Genotype influenced the extent of inhibition with GSTP1 105Val 114Ala the most sensitive to both Hg species.