Study Finds How BPA Affects Gene Expression, Anxiety; Soy Mitigates Effects

New research led by researchers at North Carolina State University shows that exposure to the chemical bisphenol A (BPA) early in life results in high levels of anxiety by causing significant gene expression changes in a specific region of the brain called the amygdala. The researchers also found that a soy-rich diet can mitigate these effects.

“We knew that BPA could cause anxiety in a variety of species, and wanted to begin to understand why and how that happens,” says Dr. Heather Patisaul, an associate professor of biology at NC State and lead author of a paper describing the work. BPA is a chemical used in a wide variety of polycarbonate plastics and epoxy resins, and is used in consumer products such as some food containers.

In the study, rats were exposed to low doses of BPA during gestation, lactation (nursing) and through puberty. One group of animals was fed only soy; one group was fed a soy-free diet; one group was fed only soy and exposed to BPA; and one group was fed no soy and exposed to BPA. Blood tests showed that the animals exposed to BPA had BPA levels well within the range found in humans. Similarly, blood tests of animals fed soy showed levels of genistein, an estrogen-like chemical found in soy, were at levels within the human range for vegetarians and others who regularly consume soy foods.

Among adolescent rats on the soy-free diet, both males and females that had been exposed to BPA exhibited significantly higher levels of anxiety. The researchers also found, for the first time, gene changes within the brain associated with this elevated anxiety.

Specifically, the study reveals that gene expression changes in the amygdala, a brain region known to play a role in mediating responses to fear and stress, are associated with the behavioral changes. Two of the affected genes were estrogen receptor beta and the melanocortin receptor 4. Both are required for oxytocin release, thus changes in oxytocin/vasopressin signaling pathways may underpin the behavioral changes. Oxytocin is a hormone and neurotransmitter that has been linked to social behavior.

However, the researchers also found that adolescent rats on the soy-rich diet did not exhibit anxiety – suggesting that the soy-rich diet may mitigate the effects of BPA. But a soy-rich diet raises questions of its own.

“Soy contains phytoestrogens that can also affect the endocrine system, which regulates hormones,” Patisaul says. “It is not clear whether these phytoestrogens are what mitigate the effect of BPA, or if it is something else entirely. That’s a question we’re hoping to address in future research.”

The paper, “Anxiogenic effects of developmental Bisphenol A exposure 1 are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy,” was published Sept. 5 in the journal PLOS ONE. The paper was co-authored by Patisaul; NC State Ph.D. student Alana Sullivan; NC State master’s student Meghan Radford; former NC State student Dr. Heather Adewale; Deena Walker and Dr. Andrea Gore of the University of Texas at Austin;  and Bozena Winnik, Janis Coughlin and Dr. Brian Buckley of Rutgers University. The research was funded by the National Institute of Environmental Health Sciences.

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Note to Editors: The study abstract follows.

“Anxiogenic effects of developmental Bisphenol A exposure 1 are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy”

Authors: Heather B. Patisaul, Alana W. Sullivan, Meghan E. Radford, Heather B. Adewale, North Carolina State University; Deena M. Walker, Andrea C. Gore, University of Texas at Austin;  Bozena Winnik, Janis L. Coughlin, Brian Buckley, Rutgers University

Published: Sept. 5 in PLOS ONE.

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 (1mg/L) from gestation through puberty, and reared on soy based or soy-free diet. A group exposed to ethinyl estradiol (50 [micrograms]/L) and 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 [estrogen receptors] 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.