Bisphenol A (BPA) is a major environmental disruptor compound and after several decades in use as a plasticizer it is present in the blood of nearly all developing and adult humans. Exposure to this endocrine- active compound alters normal hormonal function, affects neural organization and ultimately can modify behavior and lead to neurological disorders. One mechanism by which BPA may act is via decreased DNA methylation causing dysregulated gene expression. I will identify persistent, epigenetic and behavioral changes following in utero BPA exposure. The exact targets of BPA-induced hypomethylation and/or its effects on gene transcription have not been fully characterized. In these studies, I will use a dose of BPA equivalent to that noted in humans and expose mouse embryos via maternal diet. BPA-induced changes in the developing brain of these mice will be identified using genome-wide methylome profiling in Aim 1. I will confirm the epigenetic changes at the level of DNA methylation using bisulfite sequencing and measure the concordant altered gene expression. From this, I will create a prioritized gene list for validation. In our model, BPA exposure decreases methylation of estrogen receptor alpha. In order to directly identify epigenetic modifications relevant to changes associated with BPA exposure, in the second aim, I will test estrogen receptor alpha knockout mice gestated on control or BPA diets for alterations in juvenile social behaviors. These studies will aid in the identification of BPA's molecular targets and potentially uncover genes that are epigenetically changed leading to altered behavior.

Public Health Relevance

Bisphenol A (BPA) is a man-made chemical used in plastic manufacturing and is present in drinking water and plastic products such as baby bottles, food can linings and dental sealants. It is resistant to degradation and thus is the major estrogenic compound that leaches from landfills into the water supply accumulating in human blood. BPA exposure in the developing brain may epigenetically alter the expression of certain genes relevant to neurological and behavioral diseases. By studying BPA's behavioral and epigenetic effects in a developing mouse, we hope to identify pertinent epigenetic changes relevant to human neurodevelopmental disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES019404-03
Application #
8517119
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Humble, Michael C
Project Start
2011-06-15
Project End
2014-06-14
Budget Start
2013-06-15
Budget End
2014-06-14
Support Year
3
Fiscal Year
2013
Total Cost
$58,442
Indirect Cost
Name
University of Virginia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wolstenholme, Jennifer T; Goldsby, Jessica A; Rissman, Emilie F (2013) Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav 64:833-9
Wolstenholme, J T; Rissman, E F; Bekiranov, S (2013) Sexual differentiation in the developing mouse brain: contributions of sex chromosome genes. Genes Brain Behav 12:166-80