The role of Bisphenol A in shaping the brain, epigenome and behavior

Abstract

Bisphenol A (BPA) is a xenoestrogen that was first synthesized in 1891. Its estrogenic properties were discovered in 1930, and shortly after that chemists identified its usefulness in the production of epoxy resins. Since the 1950s BPA has been used as a synthetic monomer in the manufacturing of polycarbonate plastic, polystyrene resins, and dental sealants. Roughly 6.5 billion pounds of BPA are produced each year and it is the major estrogenic compound that leaches into nearby water and food supplies (vom Saal et al., 2007). BPA has been detected in 95% of human urine samples, which indicates that environmental exposure is widespread (Calafat et al., 2005). Moreover, BPA affects reproductive tissues and the brain. Thus many studies have focused on the effects of BPA during embryonic development. The most recent FDA update (Administration January 2010) points to "some concern about the potential effects of Bisphenol A on the brain, behavior, and prostate gland in fetuses, infants, and young children." In light of this concern, we present an updated review of BPA's action on the brain and behavior. We begin with a discussion of BPA's role as both an endocrine active compound and an agent that alters DNA methylation. Next, we review publications that have reported effects of BPA on brain and behavior. We end with our interpretation of these data and suggestions for future research directions.

Fig. 1

Structure of Estradiol and Bisphenol A. The chemical structures of Bisphenol A (A) and Estradiol (B) are presented. The structural similarity between the two molecules allows BPA to interact with the estrogen receptors (α and β) and other estrogen-like receptors.

Fig. 2

DNA methylation changes at the Agouti locus in the viable yellow agouti (A^vy) mouse are phenotypically detectable and environmentally influenced. Littermates from the viable yellow agouti mouse strain are pictured. Coat color varies in these mice across a spectrum from yellow to agouti. The differences in coat color are due to a change in DNA methylation at the Agouti locus. The mice that harbor loci that exhibit a low level of Agouti methylation (for example, 0%) are yellow, while mice with a high level of DNA methylation (for example, 100%) appear agouti (brown). Treatment with BPA or folic acid can shift coat color distribution toward yellow or agouti, respectively. This coat color shift persists to the next generation indicating that the epigenetic change that occurs at the agouti locus is heritable (Morgan et al. 1999; Blewitt et al. 2006). Picture adapted from (Dolinoy et al. 2006).

Fig. 3

A model of BPA’s potential modes of action. Environmental exposure to BPA affects the developing brain and behavior. Acting as an endocrine activating compound, BPA can weakly activate several estrogen (ER) and estrogen-related receptors such as ERα, ERβ, ERR-γ, membrane ER (mER) and GPR30 and/or antagonize the androgen receptor (AR). (1) BPA is a low potency activator of these receptors and may change the expression of genes containing estrogen (ERE) or androgen (ARE) response elements in comparison to the endogenous ligand. This gene activation may in turn lead to downstream epigenetic changes like DNA methylation or histone modifications which could further impact transcription. (2) At the chromatin level, BPA may act to change DNA methylation at specific loci, although the specificity and exact mechanism has not been determined (Gilbert and Liu, 2010). (3) A combined action of BPA is also possible where BPA changes the methylation state (● → ○) of specific regions of an estrogen responsive gene or (4) the genes that code for the receptors themselves, ESR1 for example, and alters its expression by changing chromatin structure and allowing the binding of transcription factors (TF). Note: There are multiple ways that each of these modes of action may act separately or in conjunction.