Interactive Effects of Prenatal Bisphenol Exposure and Postnatal Maternal Care on DNA Methylation in the Developing Brain

PROJECT SUMMARY / ABSTRACT Bisphenols (BPs) are commonly used plasticizers that are present in many plastics, such as food storage containers and reusable water bottles, as well as lining of food cans. BP exposure via oral consumption is ubiquitous in human populations with inter-individual variation in the levels of exposure. Prenatal exposure to BPs has been associated with negative neurodevelopmental and behavior outcomes for children in human epidemiological studies as well as in rodent models of prenatal BP exposure. BPs such as BPA and other “BPA-free” structural analogs, including BPF and BPS, have been shown to act as endocrine disruptors that primarily affect estrogen receptor signaling. Previous studies demonstrate that BPs can bind to both estrogen receptor alpha (ERα) and estrogen receptor beta to exert effects on gene transcription. Studies using animal models and human placental tissue have demonstrated that BPs can cross the placenta and exert effects directly on the fetus. Maternal BPs may also disrupt estrogen-dependent changes in the maternal brain which impairs postnatal maternal care. Both prenatal BP exposure and altered maternal care are associated with changes in DNA methylation levels across the genome which can lead to stable changes in transcript abundance of affected genes. However, the underlying mechanisms linking prenatal BP exposure and DNA methylation modifications at specific loci are not well-known. In addition, the relative effects of altered postnatal maternal care on offspring with prenatal BP exposure has been understudied. The primary objective of my proposed research is to examine the effects of prenatal BP exposure on DNA methylation modifications at specific loci, notably estrogen responsive elements (EREs), and corresponding changes in gene transcription in the neonatal rat brain. In addition, I will explore a potentially effective intervention, maternal licking-like tactile stimulation, to mitigate the effects of prenatal BP on DNA methylation proximal to EREs in the neonatal rat brain. I hypothesize that DNA methylation changes in response to increased prenatal BP exposure will be enriched in proximity to EREs in the neonatal rat brain and correspond to differences in transcript abundance of estrogen-responsive genes. In addition, I hypothesize that postnatal maternal licking-like stimulation would partially reverse the effects of prenatal BP exposure on DNA methylation modifications proximal to EREs in the neonatal rat brain via increased ERα binding at EREs. Training Potential: In tandem with my proposed research project, I will be developing important research competencies in the developmental origins of health and disease conceptual framework, translational research, and bioinformatic analyses of multi-omics datasets. Following these training experiences, I aim to be competitive for an independent research position and successfully transition to research independence.