The immune and neurological impacts of developmental Bisphenol A exposure in a C57bl/6 mouse model

Abstract

Environmental exposure to exogenous agents during critical time points of development may be associated with the onset of deleterious effects, including immune and neurological disorders. Numerous studies have shown that exposure to bisphenol A (BPA) can disrupt myriad biological systems. This research was focused on the immune and neurological impacts of developmental exposure to BPA both with and without an acute exposure to lipopolysaccharide (LPS) in adulthood. LPS exposure given around the time of learning "unmasks" developmental deficits in learning and memory induced by exposure to an exogenous agent earlier in life. We hypothesized that adult exposure to LPS would unmask BPA-induced developmental impacts to hippocampal-dependent learning and memory of C57BL/6 offspring. In one set of experiments, C57BL/6 female mice were exposed to 0, 25, 50, or 100 mg/kg of BPA in a corn oil vehicle by gavage, beginning at pairing with males and ending at weaning of offspring. The F1 generation were assessed on a Barnes maze at postnatal day 21 (PND21), 42, and 60. Splenic lymphocyte immunophenotype was evaluated after behavioral testing. The behavioral results from this study included high intra- and intertrial variability across ages and between sexes. While this is not unusual for this type of behavioral measure, significant differences between ages and dose groups did not conform to any observable patterns during acquisition learning. On the final reference day, exposure to BPA was associated with more correct attempts in the Barnes maze. The fewest number of correct attempts was observed in BPA-exposed females at PND60. Several significant differences in behavior were noted among age groups, and indicate that as these C57BL/6 mice aged, they responded differently to the same tasks. BPA exposure led to modified immune cell numbers at different doses and ages. Overall, this study demonstrated that BPA could alter behavior, but no consistent patterns emerged with regard to the effects of BPA dose or age at testing. In another set of experiments, pregnant C57BL/6 female mice were exposed to 0, 0.4, or 50 mg/kg of BPA in a corn oil vehicle. The resulting offspring were assessed on a Barnes maze at PND60, beginning 4 hours after a single challenge with LPS. Mice developmentally exposed to different doses of BPA made more correct escape attempts than vehicle control animals; no control groups outperformed BPA exposed groups on any behavioral measure. Control animals injected with saline significantly outperformed LPS-challenged animals. Female animals were 88% faster at this visuospatial task than males. This is inconsistent with previously reported studies where males outperform or perform equally with females on this type of evaluation. BPA exposure could be associated with impaired spatial memory in males on this task. We also reported significant changes to NK cell numbers, CD4+CD25+ T cell numbers in females and alterations to IgG in males and IL-4 in female mice. Overall, our findings suggest that developmental BPA exposure, can alter learning and immune cell types but additional research should be conducted to determine at which doses these alterations occur.