Abstract
Early life exposure to Bisphenol A (BPA), a component of polycarbonate plastics and epoxy resins, alters sociosexual behavior in numerous species including humans. The present study focused on the ontogeny of these behavioral effects beginning in adolescence and assessed the underlying molecular changes in the amygdala. We also explored the mitigating potential of a soy-rich diet on these endpoints. Wistar rats were exposed to BPA via drinking water (1 mg/L) from gestation through puberty, and reared on a soy-based or soy-free diet. A group exposed to ethinyl estradiol (50 µg/L) and a soy-free diet was used as a positive estrogenic control. Animals were tested as juveniles or adults for anxiety-like and exploratory behavior. Assessment of serum BPA and genistein (GEN), a soy phytoestrogen, confirmed that internal dose was within a human-relevant range. BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Notably, expression of estrogen receptor beta (Esr2) and two melanocortin receptors (Mc3r, Mc4r) were downregulated. Collectively, these results show that behavioral impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. These data also reveal that, because ERβ and melanocortin receptors are crucial to their function, oxytocin/vasopressin signaling pathways, which have previously been linked to human affective disorders, may underlie these behavioral outcomes.
Highlights
In species from rodents to humans, developmental exposure to endocrine disrupting compounds (EDCs) affects the emergence of sexually dimorphic behaviors sensitive to the organizational effects of steroid hormones [1]
Exposure began on gestational day (GD) 6 and continued until postnatal day (PND) 40 (GD 0 defined as day of sperm plug detection; PND 0 defined as day of birth) so that exposure covered post-implantation gestation through peri-puberty
Average daily water consumption was quantified from the pups during postnatal days 21–40, from which average daily Bisphenol A (BPA) or ethinyl estradiol (EE) was calculated
Summary
In species from rodents to humans, developmental exposure to endocrine disrupting compounds (EDCs) affects the emergence of sexually dimorphic behaviors sensitive to the organizational effects of steroid hormones [1]. In most of these prior studies, behavior was assessed in adulthood, and the specific mechanisms by which BPA altered behavior were largely unexplored. Emerging studies have associated prenatal BPA exposure with elevated hyperactivity and anxiety in young girls [4,5] suggesting the possibility that developmental exposure to BPA and other EDCs might contribute to the growing prevalence of behavioral- and mood-related disorders in children [6,7]. Work with the viable agouti mouse (Avy) has revealed that the soy phytoestrogen genistein (GEN) can counter the hypomethylating properties of BPA resulting in a coat color shift, suggesting epigenetic change as an alternative mechanism of action [16]
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