The Effects of Bisphenol A Exposure and Calbindin Knockout on Behavior, Gene Expression, and Sexual Differentiation of the Brain

Abstract

Bisphenol A (BPA) is an endocrine disrupting compound used in the production of polycarbonate plastics. Recent data have indicated health risks associated with exposure to BPA, particularly in children exposed during gestation. Gestational BPA exposure has been proposed as a risk factor for the development of neurobehavioral disorders, such as autism spectrum disorder. To address the behavioral impact of developmental exposure to BPA, I tested offspring of mice exposed to a daily low dose of BPA during pregnancy. I also asked if preconception exposure of the sire affected behaviors in offspring. Juvenile offspring exposed to BPA maternally, but not paternally demonstrated increased anxiety-like behavior. However, neither parental exposure group differed significantly from controls in the social recognition task. I also assessed the behaviors of maternally exposed offspring in two novel tasks: ultrasonic vocalizations (USVs) in pups and operant reversal learning in adults. Maternal BPA exposure increased the duration and median frequency of USVs emitted by pups during maternal separation. In the reversal learning task, females responded more accurately and earned more rewards than males and control females received more rewards than BPA females during the acquisition phase of the task. Previous research from our lab demonstrated that gestational BPA exposure not only affects offspring directly exposed in utero but also offspring three generations removed from the BPA exposure. We have previously reported that transgenerational exposure to BPA affects estrogen receptor alpha (ERα) in two sexually dimorphic brain areas. In a follow-up study, I determined the effects of ancestral BPA exposure in three sexually dimorphic brain regions: the anteroventral periventricular nucleus (AVPV), sexually dimorphic nucleus of the preoptic area (SDN-POA), and the cerebellum. In adults from F3 control and BPA lineages, I found that females had more tyrosine hydroxylase positive dopaminergic cells than males in the AVPV, particularly in cells that also had nuclei positive for ERα. Contrastingly, the volume of calbindin immunoreactivity in the SDN-POA was greater in males than females. In juvenile cerebellum, however, I found no effect of sex on the amount of calbindin protein. All three areas lacked a significant impact of transgenerational exposure to BPA. Calbindin, a high-affinity