Characterizing the Neurobiological Consequences of Perinatal Exposure to the Obesogenic Endocrine Disruptor Bisphenol-A

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MacKay, Harry




Bisphenol-A (BPA) is a component of polycarbonate and many other types of plastics. BPA has been characterized as an endocrine disruptor, most famously due to observations of its estrogenic activity in various experimental models. Because BPA is a common constituent of food and drink containers, and because it can leach out under certain conditions, human exposure is nearly ubiquitous. In this thesis, we demonstrate that CD-1 mice exposed to low, environmentally relevant doses of BPA during the perinatal period exhibit an adult phenotype characterized by sex-specific metabolic disruptions. Specifically, male mice exhibit impaired glucose tolerance, and females a propensity toward diet-induced obesity. Given the sensitivity of the hypothalamus to the organizational effects of sex steroids, we explored the possibility that early-life BPA exposure adversely affects the development of hypothalamic feeding circuitry to bring about these effects. We found that BPA- and diethylstilbestrol (DES)-exposed pups have respectively delayed and blunted postnatal leptin surges---a state of affairs that points to a role for leptin in the organizational effects of early-life xenoestrogen exposure. qRT-PCR analysis of leptin mRNA expression in white adipose tissue collected at the same time suggests that BPA and DES act at the transcriptional level to bring about these effects. Both male and female BPA-exposed mice showed a reduced density of POMC projections into the PVN. This phenotype was rescued in female BPA-exposed animals given daily injections of supplemental leptin (5 µg/g/day). Adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic POMC upregulation. Taken together, these data suggest that BPA, a known obesogen, may exert its effects through developmental programming of the hypothalamic melanocortin circuitry.






Carleton University


Abizaid, Alfondso
Patterson, Zack
Patel, Shoyeb
Khazall, Rim
Tsirlin, Dina

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