DNA methylation at birth potentially mediates the association between prenatal lead (Pb) exposure and infant neurodevelopmental outcomes

Abstract

Early-life lead (Pb) exposure has been linked to adverse neurodevelopmental outcomes. Recent evidence has indicated a critical role of DNA methylation (DNAm) in cognition, and Pb exposure has also been shown to alter DNAm. However, it is unknown whether DNAm is part of the mechanism of Pb neurotoxicity. This longitudinal study investigated the associations between trimester-specific (T1, T2, and T3) maternal blood Pb concentrations, gene-specific DNAm in umbilical cord blood, and infant neurodevelopmental outcomes at 12 and 24 months of age (mental development index, psychomotor development index, and behavioral rating scale of orientation/engagement and emotional regulation) among 85 mother–infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study. In the mediation analysis for this pilot study, P < 0.1 was considered significant. DNAm at a locus in CCSER1 (probe ID cg02901723) mediated the association between T2 Pb on 24-month orientation/engagement [indirect effect estimate 4.44, 95% confidence interval (−0.09, 10.68), P = 0.06] and emotional regulation [3.62 (−0.05, 8.69), P = 0.05]. Cg18515027 (GCNT1) DNAm mediated the association of T1 Pb [−4.94 (−10.6, −0.77), P = 0.01] and T2 Pb [−3.52 (−8.09, −0.36), P = 0.02] with 24-month EMOCI, but there was a positive indirect effect estimate between T2 Pb and 24-month psychomotor development index [1.25 (−0.11, 3.32), P = 0.09]. The indirect effect was significant for cg19703494 (TRAPPC6A) DNAm in the association between T2 Pb and 24-month mental development index [1.54 (0, 3.87), P = 0.05]. There was also an indirect effect of cg23280166 (VPS11) DNAm on T3 Pb and 24-month EMOCI [2.43 (−0.16, 6.38), P = 0.08]. These associations provide preliminary evidence for gene-specific DNAm as mediators between prenatal Pb and adverse cognitive outcomes in offspring.

Association Studies of Environmental Exposures, DNA Methylation and Children’s Cognitive, Behavioral, and Mental Health Problems

“…There have been many studies focusing on the relationships between environmental exposures and neurodevelopmental outcomes through DNA methylation. Some studies considered one single exposure and one single outcome (Engdahl et al, 2021); some studies considered one single exposure and multiple outcomes (Rygiel et al, 2021); while some studies considered multiple exposures and one single outcome (Cadiou et al, 2020). Our research is distinct from these existing studies in that we simultaneously consider a spectrum of exposures and a spectrum of correlated cognitive, behavioral, and mental health problems outcomes.…”

“…Prior studies have focused on a single exposure or a single outcome. For example, a recent study showed that DNA methylation partly mediates the association between Bisphenol F (BPF) exposure and lower cognition in boys (Engdahl et al, 2021); another study showed that DNA methylation mediated the association between early-life lead (Pb) exposure and infant neurodevelopmental outcomes such as psychomotor development index and rating scale of emotional regulation (Rygiel et al, 2021). Similarly, another study considered a single outcome, body mass index (BMI), and a spectrum of exposures, with the goal of examining whether DNA methylation mediates the relationship between an array of environmental exposures and BMI (Cadiou et al, 2020).…”

On‐going consequences of in utero exposure of Pb: An epigenetic perspective

“…Treatment with 10 μg/g Pb in the maternal patella was significantly associated with 0.61% higher methylation of IGF2 and sex‐specific 0.23% higher methylation of HSD11B2 among the female offspring (Goodrich et al, 2015). Recently, a study on the ELEMENT cohort mentioned direct evidence of prenatal Pb exposure and higher methylation patterns at CCSER1 (Rygiel et al, 2021). A different cohort study conducted on 127 pregnant mothers recruited in MINIMat food and supplementation in rural Bangladesh determined the Pb concentration in the urine (gestational week 8) and erythrocytes (gestational week 14) (Engström et al, 2015).…”

Lead‐induced neurodevelopmental lesion and epigenetic landscape: Implication in neurological disorders

“…Low levels of Pb exposure in early childhood resulted in delayed neurodevelopment in the first 7 years of life (Baghurst et al, 1992). In epidemiological cohort studies, Pb exposure during pregnancy was found to induce DNA methylation at the CpG locus, leading to impaired cognitive function in infants, with the most favorable evidence being DNA methylation of two genes, GCNT1 and CCSER1, suggesting that altered DNA methylation levels mediate the association between prenatal lead exposure and neurodevelopmental outcomes in infants (Rygiel et al, 2021). Hong et al (2021) found that the DNA methylation levels of HCP, ICP, and LCP in the chromosomal CpG region of rats exposed to Pb during pregnancy were higher than those of controls, and the methylation levels of BP‐, CC‐, and MF‐related genes were lower in the experimental group than in the control group, which indicated that maternal Pb exposure leads to impaired learning and memory functions in the offspring.…”