Interplay between prenatal bisphenol exposure, postnatal maternal care, and offspring sex in predicting DNA methylation relevant to anxiety-like behavior in rats

Prenatal exposure to endocrine disrupting chemicals, such as bisphenols, can alter neurodevelopmental trajectories and have a lasting neurobehavioral impact through epigenetic pathways. However, outcomes associated with prenatal bisphenol exposure may also be shaped by the postnatal environment and collectively these environmental effects may be sex-specific. Thus, an integrative research design that includes multiple early life exposures and considers sex differences may be essential for predicting outcomes. In the current study, we use a multivariate approach to examine the contributions of prenatal bisphenol exposure, postnatal maternal care, and offspring sex to variation in DNA methylation of well-studied candidate genes (NR3C1, BDNF, OXTR) in the ventral hippocampus and amygdala of adult Long-Evans rats. Main effects of postnatal maternal care and interactions with prenatal bisphenol exposure were consistently found for DNA methylation within the NR3C1 gene (ventral hippocampus) and within the BDNF and OXTR genes (amygdala). Sex-specific effects were also found across all analyses. Overall, our findings suggest that both early-life factors (prenatal and postnatal) and offspring sex contribute to variation in DNA methylation in genes and brain regions relevant for the expression of anxiety-like behavior. These results highlight the need to consider the brain region-specific effects of multiple exposures in males and females to understand the lasting effects of early environments.