Low levels of bisphenol A (BPA;2,2-bis(4-hydroxyphenyl)propane) are detectable throughout the US population. Whether these low levels of exposure pose a human health risk remain controversial and uncertain. Comparable low levels of BPA cause behavioral abnormalities in adult rodents exposed during critical periods of central nervous system (CNS) development, leading the National Toxicology Program to recently report concern that low dose BPA exposure can impair CNS development. The predominant assumption that BPA exerts its CNS effects through estrogen receptor (ER) activation is unlikely due to BPA's weak binding affinity for classical ERs. However, BPA exhibits 100- to 10,000-fold greater binding affinity for estrogen related receptor gamma (ERR3). ERR3 is a nuclear receptor that is highly expressed in the brain and placenta during critical periods of development, has no known endogenous ligand, and is constitutively active at estrogen response elements (EREs). This proposal will test the hypothesis that low dose developmental BPA exposure perturbs CNS development and behavior by maintaining ERR3 constitutive activity during critical windows of development resulting in abnormal expression of genes containing EREs or ERREs. Preliminary studies conducted to support this two year exploratory grant suggest that developmental exposure to non-teratogenic, low concentrations (<1
In recent years the public and the scientific community have become concerned with the risk that bisphenol A (BPA) may pose to human health. This project will use the unique advantages of the embryonic zebrafish model to dissect the mechanism by which low concentrations of BPA interact with and perturb central nervous development and function.
|Weber, Daniel N; Hoffmann, Raymond G; Hoke, Elizabeth S et al. (2015) Bisphenol A exposure during early development induces sex-specific changes in adult zebrafish social interactions. J Toxicol Environ Health A 78:50-66|
|Saili, Katerine S; Tilton, Susan C; Waters, Katrina M et al. (2013) Global gene expression analysis reveals pathway differences between teratogenic and non-teratogenic exposure concentrations of bisphenol A and 17?-estradiol in embryonic zebrafish. Reprod Toxicol 38:89-101|
|Saili, Katerine S; Corvi, Margaret M; Weber, Daniel N et al. (2012) Neurodevelopmental low-dose bisphenol A exposure leads to early life-stage hyperactivity and learning deficits in adult zebrafish. Toxicology 291:83-92|