Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead

Abstract

Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1,623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend towards negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice.

Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood

“…In a study using similar Pb exposures as used here, female but not male mice exhibited hypermethylation; however, no significant changes in whole-genome DNA methylation were found in cortex in that study (Sanchez-Martin et al, 2015). Similarly, sex differences in response to PS have been described.…”

Perinatal lead (Pb) exposure results in sex and tissue‐dependent adult DNA methylation alterations in murine IAP transposons

“…This finding is not altogether surprising as we have shown previously that the A vy allele, a well studied IAP element, also displays a nonmonotonic response to neonatal Pb exposure (Faulk et al, ). Sanchez‐Martin et al also observed nonmonotonic Pb‐induced changes in DNA methylation, which modestly correlated with mRNA expression, and these observations were similarly made in the mouse brain, specifically the hippocampus (Sanchez‐Martin et al, ).…”

Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism

“…Brain cortex and hippocampus were collected from offspring at PND60 and evaluated using epigenome-wide DNA methylation and RT qPCR for targeted gene expression. In both exposure groups compared to controls, females but not males displayed hypermethylated regions of the hippocampus [49]. Further, in the low exposure group there was a trend for females only toward a correlation between the observed three differentially methylation regions and changes in gene expression levels of the sixty genes selected for validation.…”