Prenatal exposure to mercury, a known neurotoxic metal, is associated with lower cognitive performance during childhood. Disruption of fetal epigenetic programming could explain mercury's neurodevelopmental effects. We screened for epigenome-wide methylation differences associated with maternal prenatal blood mercury levels in 321 cord blood DNA samples and examined the persistence of these alterations during early (n = 75; 2.9-4.9 years) and mid-childhood (n = 291; 6.7-10.5 years). Among males, prenatal mercury levels were associated with lower regional cord blood DNA methylation at the Paraoxonase 1 gene (PON1) that persisted in early childhood and was attenuated in mid-childhood blood. Cord blood methylation at the PON1 locus predicted lower cognitive test scores measured during early childhood. Methylation at the PON1 locus was associated with PON1 expression in an independent set of cord blood samples. The observed persistent epigenetic disruption of the PON1 gene may modulate mercury toxicity in humans and might serve as a biomarker of exposure and disease susceptibility.

Background

Mercury is a global pollutant, and prenatal exposure is associated with adverse health effects. To date, no studies have evaluated the association between prenatal mercury exposure and DNA hydroxymethylation, an epigenetic modification important for tissue differentiation and embryonic development.

Objectives

We sought to evaluate the association between prenatal mercury exposure and offspring global DNA methylation and hydroxymethylation at birth and test for persistence of the association in childhood.

Methods

Within Project Viva, a U.S. prebirth cohort, we examined associations of maternal second trimester red blood cell mercury (RBC-Hg) concentrations with global 5-hydroxymethylcytosine (%-5hmC) and 5-methylcytosine (%-5mC) DNA content in blood collected at birth (n=306), early childhood (n=68; 2.9 to 4.9 y), and midchildhood (n=260; 6.7 to 10.5 y).

Results

Median prenatal RBC-Hg concentration was 3.23μg/g [interquartile range (IQR)=3.29]. At birth, median cord blood %-5mC, %-5hmC, and their ratio were 4.95%, 0.22%, and 24.37, respectively. The mean adjusted difference [95% confidence interval (CI)] of blood %-5hmC for a doubling in prenatal RBC-Hg concentration was -0.013% (-0.029, 0.002), -0.031% (-0.056, -0.006), and 0.005% (-0.007, 0.018) at birth, early, and midchildhood, respectively. The corresponding relative adjusted change in the genomic ratio of %-5mC to %-5hmC for a doubling in prenatal RBC-Hg concentration was 4.70% (0.04, 9.58), 22.42% (7.73, 39.11), and 0.73% (-4.18, 5.88) at birth, early, and midchildhood, respectively. No associations were present between prenatal maternal RBC-Hg and %-5mC at any time point.

Conclusions

Prenatal mercury exposure was associated with lower %-5hmC genomic content and a corresponding increase in the ratio of %-5mC to %-5hmC in cord blood. This association was persistent in early but not midchildhood blood. Our results demonstrate the potential malleability of epigenetic modifications associated with mercury exposure in utero. https://doi.org/10.1289/EHP1467.