Interaction of mercury exposure and DNA methylation with sustained attention in children in a novel analysis of epigenetic susceptibility

Abstract

The etiology of attention-deficit/hyperactivity disorder (ADHD) remains poorly understood, despite it being one of the most common neurodevelopmental disorders worldwide. Past research suggests methylmercury exposure and DNA methylation (DNAm) levels are each associated with ADHD in children, yet whether they interact to affect ADHD is unknown. Leveraging data from a longitudinal cohort of children in Mexico, this novel epigenetic-environment interaction study identified significant interactions between childhood mercury exposure (measured at 6-12 years of age) and adolescent blood leukocyte DNAm in their association with sustained attention [quantified via the Conners continuous performance test, 3rd edition (CPT3)] measured on average 5.6 ± 0.99 years later. Using adjusted linear regression, we assessed associations between hair and urine mercury concentrations and CPT3 scores reflecting inattention, impulsivity, vigilance, and sustained attention (N = 399). We then tested the interaction between mercury and DNAm at loci previously associated with the CPT3 outcomes (N = 374). Significant associations between mercury and CPT3 differed in magnitude and direction depending on the mercury biomarker and CPT3 variable. These associations often differed by gender. For example, urine mercury was positively associated with vigilance scores in males [β = 1.31(SE = 0.65), P = .045] but not in females [β = -0.20 (SE = 0.81), P = .80). In all children, three significant mercury-DNAm interactions were identified for either inattention or vigilance outcomes. Among females, 155 significant interaction terms were identified for the inattention models. In males, three significant interactions were identified for the impulsivity model. Overall, results suggest in some cases DNAm can influence the association between mercury exposure and ADHD-like symptoms.

Keywords: children’s health; epigenetics; gene-environment; mercury.

Figure 1.

Schematic of the timing of key predictors and outcomes in ELEMENT that are the focus of this research. The inner box outlines the timepoints, variables, and sample size relevant to model 1 and the outer box represents those pertinent to model 2. Note that blood DNAm and CPT3 performance were measured at the same time point while Hg was measured in samples collected several years prior.

Figure 2.

Schematic representing the possible relationships between Hg, DNAm, and CPT3 performance. (a) In the case of epigenetic susceptibility, Hg and DNAm could have independent effects on the CPT3 outcome and the interaction between the two has an additional effect when both are present. (b) In the case of mediation, DNAm is a mediator in the relationship between Hg exposure and CPT3 performance.