Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice.

Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical. Developmental exposure produces changes in behavior and gene expression in the brain. Here, we examined social recognition behaviors in mice from the third familial generation (F3) after exposure to gestational BPA. Second-generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory postsynaptic densities (PSDs) were examined in F3 brains using quantitative PCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes-SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95)-were differentially expressed in control- vs BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established, and our data suggest that BPA may contribute in a transgenerational manner to neurodevelopmental diseases.

Multi- and Transgenerational Consequences of Bisphenol A on Sexually Dimorphic Cell Populations in Mouse Brain.

Bisphenol A (BPA) is an endocrine-disrupting compound used to manufacture plastics; it is present in linings of food cans, bottles, thermal receipts, and many other everyday items and is detectable in human urine and blood. Exposure to BPA during development can disrupt sexual differentiation of some brain regions. Moreover, BPA can have transgenerational effects on gene expression and behaviors. Here, we used a diet and breeding regimen that produces transgenerational effects on behaviors. C57BL/6J mice consumed control or BPA-containing diets during pregnancy. We examined vasopressin (AVP) and estrogen receptor α (ERα) immunoreactivity (ir) in sexually dimorphic brain regions from first-generation (F1) offspring and transgenerational effects of BPA in third-generation offspring. In all but one brain region examined, the expected sex differences were noted in both generations of control mice. In F1 mice, a diet by sex interaction was present for AVP-ir in the lateral septum and posterodorsal medial amygdala. In both regions, BPA exposure reduced immunoreactivity in male brains. An interaction between diet and sex for ERα-ir in the ventromedial hypothalamus was caused by reduced immunoreactivity in BPA-exposed females. Of interest, BPA had transgenerational effects on ERα-ir in the anteroventral periventricular nucleus and bed nucleus of the stria terminalis. Our data show that BPA produces immunoreactive differences in ERα-ir generations after exposure to BPA. We speculate that actions of BPA in utero on ERα-ir in brain have long-term consequences for reproduction and social behavior.

Transgenerational effects of prenatal bisphenol A on social recognition.

Bisphenol A (BPA) is a man-made endocrine disrupting compound used to manufacture polycarbonate plastics. It is found in plastic bottles, canned food linings, thermal receipts and other commonly used items. Over 93% of people have detectable BPA levels in their urine. Epidemiological studies report correlations between BPA levels during pregnancy and activity, anxiety, and depression in children. We fed female mice control or BPA-containing diets that produced plasma BPA concentrations similar to concentrations in humans. Females were mated and at birth, pups were fostered to control dams to limit BPA exposure to gestation in the first generation. Sibling pairs were bred to the third generation with no further BPA exposure. First (F1) and third (F3) generation juveniles were tested for social recognition and in the open field. Adult F3 mice were tested for olfactory discrimination. In both generations, BPA exposed juvenile mice displayed higher levels of investigation than controls in a social recognition task. In F3 BPA exposed mice, dishabituation to a novel female was impaired. In the open field, no differences were noted in F1 mice, while in F3, BPA lineage mice were more active than controls. No impairments were detected in F3 mice, all were able to discriminate different male urine pools and urine from water. No sex differences were found in any task. These results demonstrate that BPA exposure during gestation has long lasting, transgenerational effects on social recognition and activity in mice. These findings show that BPA exposure has transgenerational actions on behavior and have implications for human neurodevelopmental behavioral disorders.