An Investigation of Modifying Effects of Metallothionein Single-Nucleotide Polymorphisms on the Association between Mercury Exposure and Biomarker Levels

Abstract

Background: Recent studies have suggested that several genes that mediate mercury metabolism are polymorphic in humans.Objective: We hypothesized that single-nucleotide polymorphisms (SNPs) in metallothionein (MT) genes may underlie interindividual differences in mercury biomarker levels. We studied the potential modifying effects of MT SNPs on mercury exposure–biomarker relationships.Methods: We measured total mercury in urine and hair samples of 515 dental professionals. We also surveyed occupational and personal exposures to dental amalgam and dietary fish consumption, from which daily methylmercury (MeHg) intake was estimated. Log-transformed urine and hair levels were modeled in multivariable linear regression separately against respective exposure surrogates, and the effect modification of 13 MT SNPs on exposure was investigated.Results: The mean mercury levels in urine (1.06 μg/L) and hair (0.51 μg/g) were not significantly different from the U.S. general population (0.95 μg/L and 0.47 μg/g, respectively). The mean estimated daily MeHg intake was 0.084 μg/kg/day (range, 0–0.98 μg/kg/day), with 25% of study population intakes exceeding the current U.S. Environmental Protection Agency reference dose of 0.1 μg/kg/day. Multivariate regression analysis showed that subjects with the MT1M (rs2270837) AA genotype (n = 10) or the MT2A (rs10636) CC genotype (n = 42) had lower urinary mercury levels than did those with the MT1M or MT2A GG genotype (n = 329 and 251, respectively) after controlling for exposure and potential confounders. After controlling for MeHg intake, subjects with MT1A (rs8052394) GA and GG genotypes (n = 24) or the MT1M (rs9936741) TT genotype (n = 459) had lower hair mercury levels than did subjects with MT1A AA (n = 113) or MT1M TC and CC genotypes (n = 15), respectively.Conclusion: Our findings suggest that some MT genetic polymorphisms may influence mercury biomarker concentrations at levels of exposure relevant to the general population.

Genetic polymorphisms affecting susceptibility to mercury neurotoxicity in children: Summary findings from the Casa Pia Children's Amalgam Clinical Trial

“…Two MT isoforms, MT1 and MT2, in particular, are implicated in the dispersal and storage of Hg in the CNS (West et al, 2008). Studies in humans have suggested that SNPs of these MT isoforms, MT1M (rs2270837) and MT2A (rs10636), affect Hg body burden, and therefore potentially modify the adverse effects of Hg on neurobehavioral functions (Gundacker et al, 2007; Wang et al, 2012). Testing this hypothesis in children, we observed numerous significant adverse effects, particularly in relation to chronic Hg exposure, among boys genotyped as HetMut for either MT1M or MT2A, occurring principally within the domains of Visual Spatial acuity and Learning & Memory, but also on tests of Attention and Motor function (Table 4).…”

“…Of note, Hg 2+ directly impairs the enzymatic activity of CPOX4 (Li and Woods, 2009) and also likely inhibits preferentially the S-containing met forms of the COMT val158met enzyme and the BDNF val66met protein product, both of which play critical roles in neurologic development (Barnett et al, 2009; Burkhalter et al, 2003). Moreover, genetic variants affecting Hg toxicokinetics, e.g., MT1M, MT2A, GSTT1 (Wang et al, 2012), might predispose children to higher concentrations of Hg in critical brain regions than would occur in adults with comparable exposures. Such effects directed against components of the developing central nervous system could underlie the preferential susceptibility of children and adolescents with these genotypes to the adverse neurologic effects of Hg exposure.…”

“…Such studies are relevant, however, in light of recent findings (Basu, et al, 2013; Echeverria et al, 2005, 2006, 2010; Goodrich et al, 2011; Gundacker et al, 2007, 2009; Heyer et al, 2004, 2008, 2009; Schläwicke Engstrom et al, 2008; Wang et al, 2012) identifying common variants of numerous genes that modify the effects of Hg on neurologic functions and/or Hg handling in human subjects. Identification of genetic polymorphisms that affect Hg neurotoxicity is of particular importance with regard to assessment of Hg risks in children, who may be uniquely susceptible, compared with adults, because of their smaller body mass and more rapidly developing, hence more fragile, nervous and metabolic systems (Landrigan and Goldman, 2011).…”

Mercury-induced motor and sensory neurotoxicity: systematic review of workers currently exposed to mercury vapor

“…The low-level exposures from mercury-containing dental amalgam result in urine Hg levels that overlap those of the US general population (Wang et al 2012). Moreover, many dentists and dental technicians have occupational exposures to other neurotoxic agents, including nitrous oxide (National Institute for Occupational Safety and Health (NIOSH) 2015), an anesthetic associated with impaired neurobehavioral performance (Lucchini et al 1996) and increased risk of neurological disease (Cohen et al 1980), and methyl methacrylate, a monomer widely used in dentistry that has been associated with sensorimotor neuropathy (Verkkala et al 1983; Seppalainen and Rajaniemi 1984; Rajaniemi 1986).…”

Відмінності Вмісту Металотіонеїну У Мозку Гризунів За Умов Постнатального Розвитку Та Кадмієвої Інтоксикації

“…Cd exposure results in pathological conditions in the liver, testis, brain, and nervous system, kidney, spleen, and bone marrow, locations that have been shown to express MT upon induction. Its exposure can also lead to apoptosis in testes of rat, mouse liver, and human T-cells [16]. Having re gistered continuously decreasing MT concentrations in the brain under two different low doses of Cd, we observed that MT plays a vital role in heavy metal regulation.…”