Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure

Environmental factors play an important role in the etiology of cardiovascular diseases. Cardiovascular diseases exhibit marked sexual dimorphism; however, the sex-specific effects of environmental exposures on cardiac health are incompletely understood. Perinatal and adult exposures to the metal lead (Pb) are linked to several adverse cardiovascular outcomes, but the sex-specific effects of this toxicant on the heart have received little attention. Perinatal environmental exposures can lead to disease through disruption of the normal epigenetic programming that occurs during early development. Using a mouse model of human-relevant perinatal environmental exposure, we investigated the effects of exposure to Pb during gestation and lactation on DNA methylation in the hearts of adult offspring mice (n = 6 per sex). Two weeks prior to mating, dams were assigned to control or Pb acetate (32 ppm) water, and exposure continued until offspring were weaned at three weeks of age. Enhanced reduced-representation bisulfite sequencing was used to measure DNA methylation in the hearts of offspring at five months of age. Although Pb exposure stopped at three weeks of age, we discovered hundreds of differentially methylated cytosines (DMCs) and regions (DMRs) in males and females at five months of age. DMCs/DMRs and their associated genes were sex-specific, with a small, but statistically significant subset overlapping between sexes. Pathway analysis revealed altered methylation of genes important for cardiac and other tissue development in males, and histone demethylation in females. Together, these data demonstrate that perinatal exposure to Pb induces sex-specific changes in cardiac DNA methylation that are present long after cessation of exposure, and highlight the importance of considering sex in environmental epigenetics and mechanistic toxicology studies.