Effects of Adult Exposure to Bisphenol A on Genes Involved in the Physiopathology of Rat Prefrontal Cortex

Abstract

Several neurological and behavioral dysfunctions have been reported in animals exposed to bisphenol A (BPA). However, little is known about the impact of adult exposure to BPA on brain physiopathology. Here, we focused on prefrontal cortex (PFC) of rats, because it is an important area for cognitive control, complex behaviors and is altered in many psychopathologies. Gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems are essential for PFC function. Therefore, we examined the effects of adult exposure to BPA on 5α-Reductase (5α-R) and cytochrome P450 aromatase (P450arom), enzymes that synthesize GABAA receptor modulators, and tryptophan hydroxylase (Tph), the rate-limiting enzyme in 5-HT biosynthesis. To gain better understanding of BPA’s action in the adult PFC, 84 genes involved in neurotoxicity were also analysed. Adult male and female rats were subcutaneously injected for 4 days with 50 µg/kg/day, the current reference safe dose for BPA. mRNA and protein levels of 5α-R, P450arom and Tph were quantified by real-time RT-PCR and Western blot. Genes linked to neurotoxicity were analyzed by PCR-Array technology. Adult exposure to BPA increased both P450arom and Tph2 expression in PFC of male and female, but decreased 5α-R1 expression in female. Moreover, we identified 17 genes related to PFC functions such as synaptic plasticity and memory, as potential targets of BPA. Our results provided new insights on the molecular mechanisms underlying BPA action in the physiopathology of PFC, but also raise the question about the safety of short-term exposure to it in the adulthood.

Bisphenol A, bisphenol F and bisphenol S affect differently 5α-reductase expression and dopamine–serotonin systems in the prefrontal cortex of juvenile female rats

“…In this work, BPA decreased 5α-R2 mRNA and protein levels without affecting 5α-R1 expression, which differs from our previous findings in adult rats treated for four days with 50 mg BPA/ kg/d (Castro et al, 2013b). These discrepancies may reflect temporal or compensatory effects as a result of differential exposure times, or dose-dependent mechanisms (Vandenberg et al, 2012).…”

“…3α,5α-NS modulate emotional responses and cognitive function (Frye, 2009;Paris et al, 2011b), which are mediated in part by the PFC (Davidson, 2002;Paris et al, 2011b). With this in mind and the finding that short-term exposure to BPA affects 5α-R levels in the PFC of adult female rats (Castro et al, 2013b), we believe that this enzyme might be a potential target for BPA-mediated effects in the female perinatal brain.…”

“…Our previous findings indicated that adult exposure to BPA decreases the expression of 5α-R isozymes type 1 and type 2 in the prostate of rats (Castro et al, 2013a). In contrast, BPA failed to modify 5α-R expression in the prefrontal cortex (PFC) of adult (Castro et al, 2013b) or juvenile (Castro et al, 2015) male rats. Besides dihydrotestosterone (DHT) synthesis, 5α-R is the rate-limiting enzyme in the biosynthesis of 3α,5α-reduced neurosteroids (3α,5α-NS), such as allopregnanolone (AlloP).…”

Bisphenol A disrupts gene expression in human placental trophoblast cells

“…Therefore, our present demonstration of BPA stimulation of aromatase expression may have significant implications for the function of estrogens during pregnancy. Although our present findings are in contrast to those reported previously of decreased aromatase activity and expression in JEG-3 cells [33,35], they are consistent with those of numerous in vitro and in vivo studies [48][49][50][51][52][53][54][55]. For example, BPA exposure has been shown to increase aromatase expression in the rat brain [50,53], ovary [51] and prostate [54].…”

Identification of dopamine- and serotonin-related genes modulated by bisphenol A in the prefrontal cortex of male rats

“…Recent findings regarding BPA neurotoxicity have indicated that this endocrine disruptor produces brain region-specific changes in dopaminergic processes, resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse (Jones and Miller, 2008;Narita et al, 2006). Moreover, we and others have pointed out that BPA might also affect the serotoninergic system (Castro et al, 2013;Matsuda et al, 2010Matsuda et al, , 2013.…”