Abstract

Bisphenol-A (BPA) is a component of polycarbonate and other plastics to which humans are regularly exposed at low levels. BPA is characterized as an endocrine disruptor due to observations of its estrogenic activity in various experimental models. We have previously shown evidence of disrupted hypothalamic feeding circuitry and leptin sensitivity in adult BPA-exposed animals subject to a high-fat diet, but because these animals were already exhibiting a diet-induced obese phenotype, we could not rule out the possibility that these observations were simply consequences of the obesity, not a pre-existing phenotype produced by BPA exposure. Here we study leptin sensitivity and hypothalamic structure in young BPA-exposed animals prior to the onset of a body weight or metabolic phenotype. Pregnant and lactating CD-1 mice were exposed to either BPA or diethylstilbestrol (DES) at low, environmentally relevant doses via their diet. Studies of leptin function and neurobiology were conducted on offspring at a number of timepoints. Young adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic POMC upregulation. Both male and female BPA-exposed mice showed a reduced density of Pro-Opiomelanocortin (POMC) projections into the paraventricular hypothalamus (PVN). BPA-and DES-exposed pups had respectively delayed and blunted postnatal leptin surges, and POMC projections into the PVN were rescued in female BPA-exposed animals given daily injections of supplemental leptin. Our findings suggest that BPA, a putative obesogen, may exert its effects through developmental programming of the hypothalamic melanocortin circuitry, permanently altering the neurobiology of metabolic homeostasis.

Author notes

Corresponding author and to whom reprint requests should be addressed: Alfonso Abizaid Ph.D., alfonso.abizaidbucio@carleton.ca, Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, 613-520-2600 x1544

Supplementary data