Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice

Bisphenol A (BPA) is a man-made compound used to make polycarbonate plastics and epoxy resins; public health concerns have been fueled by findings that BPA exposure can reduce sex differences in brain and some behaviors. We asked if a low BPA dose, within the range measured in humans, ingested during pregnancy, would affect social behaviors in prepubertal mice. We noted sex differences in social interactions whereby females spent more time sitting side-by-side, while males engaged in more exploring and sitting alone. In addition BPA increased display of nose-to-nose contacts, play solicitations and approaches in both sexes. Interactions between sex and diet were found for self grooming, social interactions while sitting side-by-side and following the other mouse. In all these cases interactions were produced by differences between control and BPA females. We examined brains from embryos during late gestation to determine if gene expression differences might be correlated with some of the sexually dimorphic or BPA affected behaviors we observed. Because BPA treatments ended at birth we took the brains during embryogenesis to increase the probability of discovering BPA mediated effects. We also selected this embryonic age (E18.5) because it coincides with the onset of sexual differentiation of the brain. Interestingly, mRNA for the glutamate transporter, Slc1a1, was enhanced by exposure to BPA in female brains. Also we noted that BPA changed the expression of two of the three DNA methyltransferase genes, Dnmt1 and Dnmt3a. We propose that BPA affects DNA methylation of Sc1a1 during neural development. Sex differences in juvenile social interactions are affected by BPA and in particular this compound modifies behavior in females

Mean +/- SEM behaviors displayed during a reciprocal social interaction task.

<p>Juvenile male and female mice were exposed to control (phytoestrogen-free chow, black histograms, n = 15 males and n = 13 females) or BPA supplemented chow (gray histograms, n = 21 males and n = 18 females) during gestation. <b>A</b>) Total amount of time in seconds spent exploring the cage. <b>B</b>) Duration of side by side sitting (seconds). <b>C</b>) Amount of time spent self grooming (seconds). <b>D</b>) Duration of side by side interactions (seconds). * Sex effect; males are significantly different from females, p<0.05. ^# Significantly different from control females, p<0.05.</p

Mean +/− SEM time spent (in seconds) or frequencies of different types of behavior in a 30- minute social interaction test.

<p>! Significant effect of sex p<0.05,</p><p>* Significantly different from the same sex control p<0.05,</p><p># Significant effect of diet p<0.05.</p

Mean +/− SEM time spent in different sections of the elevated plus maze during a 10 minute test.

<p>No significant differences were found in any anxiety phenotype in juvenile mice exposed to BPA.</p

Mean +/- SEM for gene expression in E18.5 brains relative to control males and normalized to beta-2-microglobulin or beta-actin.

<p><i>Esr1</i>  =  estrogen receptor alpha, <i>Esr2</i>  =  estrogen receptor beta, <i>Gper</i>  =  G protein-coupled estrogen receptor, <i>Dnmt3b</i>  =  DNA methyltransferase 3b, <i>Gria1</i>  =  AMPA ionotropic glutamate receptor, <i>Grin2a</i>  =  NMDA receptor subunit 2a, <i>Grin2b</i>  =  NMDA receptor subunit 2b.</p><p>These genes were not significantly altered by BPA exposure or sex. N = 5–6 brains in each group.</p

Primer Sequences for SYBR Green qPCR assays.

<p>Primer Sequences for SYBR Green qPCR assays.</p