Modification of neurobehavioral effects of mercury by genetic polymorphisms of metallothionein in children

Abstract

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that genetic variants of metallothionein (MT) that are reported to affect Hg toxicokinetics in adults would modify the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the completion of the clinical trial, we performed genotyping assays for variants of MT isoforms MT1M (rs2270837) and MT2A (rs10636) on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant interactions or independent main effects for Hg exposure and either of the MT gene variants were observed. In contrast, among boys, numerous significant interaction effects between variants of MT1M and MT2A, alone and combined, with Hg exposure were observed spanning multiple domains of neurobehavioral function. All dose-response associations between Hg exposure and test performance were restricted to boys and were in the direction of impaired performance. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with relatively common genetic variants of MT, and may have important public health implications for future strategies aimed at protecting children and adolescents from the potential health risks associated with Hg exposure. We note that because urinary Hg reflects a composite exposure index that cannot be attributed to a specific source, these findings do not support an association between Hg in dental amalgams specifically and the adverse neurobehavioral outcomes observed.

Keywords: Behavior; Children; Genetic polymorphism; Hg; IQ; MT; MT1M; MT2A; Mercury; Metallothionein; Neurotoxicity; SNP; intelligence quotient; mercury; metallothionein; metallothionein class 2, isoform A; metallothionein class1, isoform M; single nucleotide polymorphism.

Figure 1

Associations between performance on the Stroop Color test and Hg exposure among boys. Scatter plots and simple linear regression fit lines of Stroop Color test scores by cumulative Hg exposure (ln[(ΣHgU)+1]) are plotted to distinguish boys with double wildtype (WT) (open dots, dotted line) or double HetMut allelic status (closed dots, solid line) for the two MT genes.

Figure 2

Associations between performance on the Digit Symbol test and Hg exposure among boys. Scatter plots and simple linear regression fit lines of the Digit Symbol test scores by cumulative Hg exposure (ln[(ΣHgU)+1]) are plotted to distinguish boys with double wildtype (WT) (open dots, dotted line) or double HetMut allelic status (closed dots, solid line) for the two MT genes.