Perinatal Exposure to Low-Dose Bisphenol-A Disrupts the Structural and Functional Development of the Hypothalamic Feeding Circuitry.
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 because of 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 subjected 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 preexisting phenotype produced by BPA exposure. Here, we studied leptin sensitivity and hypothalamic structure in young BPA-exposed animals before 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 several time points. Young adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic pro-opiomelanocortin (POMC) upregulation. Both male and female BPA-exposed mice showed a reduced density of POMC projections into the paraventricular nucleus of the 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.
Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
Harry
H
MacKay
Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
Zachary R
ZR
Patterson
Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
Alfonso
A
Abizaid
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D052244:Endocrine Disruptors / Q000494:pharmacology*; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000494:pharmacology; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D020738:Leptin; D010636:Phenols; D011333:Pro-Opiomelanocortin; C006780:bisphenol A; D000098826:Bisphenol A Compounds