Genetic Predisposition to Prenatal Methylmercury Toxicity and Child Cognitive Development at Age 8 Years

Abstract

Background: The association of childhood cognitive function and prenatal exposure to methylmercury was previously found to be modified by genetic variation. We further explored the potential genetic predisposition in an extended study of children from the Avon Longitudinal Study of Parents and Children (Bristol, UK) (ALSPAC). Methods: A subgroup (n = 1 127 from the pilot study and 1 045 from the present study) of the ALSPAC cohort was identified based on the availability of the mercury (Hg) concentration of umbilical cord tissue as a measure of prenatal methylmercury exposure, data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as scores on the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) at age 8 years. Multivariable regression models were used to assess the associations between methylmercury exposure and IQ as a cognitive development measure and to determine possible gene-environment interactions. Inclusion of covariate variables reduced the total sample size from 2 172 to 1 723 complete cases; inverse probability weighting was applied in final models. Findings: At the low exposure level in this population, the log10-transformed mercury concentration was positively associated with IQ, but adjustment for nutritional and sociodemographic cofactors attenuated this association. Inclusion of selenium and vitamin D measured in pregnancy blood samples did not affect these findings. Enhanced interaction with methylmercury neurotoxicity was replicated in the new study for the minor allele of rs1042838 (progesterone receptor) (Beta; 95% Confidence Interval) = (-11.8; -23.0 to -0.7) (P-for-interaction = 0.004) and less clearly for rs662 (paraoxonase 1) (-3.6; -11.5 to 4.2) (P = 0.115). In the joint sample, new potential interacting SNPs were discovered in relation to superoxide dismutase 2, ATP binding cassette subfamily A member 1 and metallothionein 1M genes. Interpretation: Low-level prenatal exposure to methylmercury was weakly, though positively, associated with child cognitive development 8 years later. However, for PGR rs1042838, the presence of the minor allele revealed a clear negative association of mercury exposure with IQ. These findings emphasize that understanding of methylmercury neurotoxicity can be enhanced by integrating genetic data into the analysis. Funding Statement: Spanish Institute of Health Carlos III. Declaration of Interests: The authors have no conflicts of interest to declare. All the authors have no financial relationships relevant to this article to disclose. Ethics Approval Statement: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.