title: Organizational effects of perinatal exposure to bisphenol-A and diethylstilbestrol on arcuate nucleus circuitry controlling food intake and energy expenditure in male and female CD-1 mice.
abstract: The endocrine disrupting compound bisphenol-A (BPA) has been reported to act as an obesogen in rodents exposed perinatally. In this study, we investigated the effects of early-life BPA exposure on adult metabolic phenotype and hypothalamic energy balance circuitry. Pregnant and lactating CD-1 dams were exposed, via specially prepared diets, to 2 environmentally relevant doses of BPA. Dams consumed an average of 0.19 and 3.49 μg/kg per day of BPA in the low and high BPA treatments prenatally and an average of 0.36 and 7.2 μg/kg per day of BPA postnatally. Offspring were weaned initially onto a normal (AIN93G) diet, then as adults exposed to either a normal or high-fat diet (HFD). Males exposed to the high dose of BPA showed impaired glucose tolerance on both diets. They also showed reduced proopiomelanocortin fiber innervation into the paraventricular nucleus of the hypothalamus, and when exposed to HFD, they demonstrated increased neuropeptide Y and Agouti-related peptide expression in the arcuate nucleus (ARC). Females exposed to the high BPA dose were heavier, ate more, and had increased adiposity and leptin concentrations with reduced proopiomelanocortin mRNA expression in the ARC when consuming a HFD. BPA-exposed females showed ARC estrogen receptor α expression patterns similar to those seen in males, suggesting a masculinizing effect of BPA. These results demonstrate that early-life exposure to the obesogen BPA leads to sexually dimorphic alterations in the structure of hypothalamic energy balance circuitry, leading to increased vulnerability for developing diet-induced obesity and metabolic impairments, such as glucose intolerance.
authors.affiliation: Carleton University, Department of Neuroscience, Ottawa, Ontario, Canada K1S 5B6.
authors.forename: Harry
authors.initials: H
authors.lastname: Mackay
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Patterson
authors.forename: Rim
authors.initials: R
authors.lastname: Khazall
authors.forename: Shoyeb
authors.initials: S
authors.lastname: Patel
authors.forename: Dina
authors.initials: D
authors.lastname: Tsirlin
authors.forename: Alfonso
authors.initials: A
authors.lastname: Abizaid
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000009:adverse effects*; D059305:Diet, High-Fat; D004054:Diethylstilbestrol / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000009:adverse effects*; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005951:Glucose Tolerance Test; D008297:Male; D051379:Mice; D009412:Nerve Fibers / Q000187:drug effects; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011333:Pro-Opiomelanocortin / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D015430:Weight Gain / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004054:Diethylstilbestrol; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D010636:Phenols; D011333:Pro-Opiomelanocortin; C006780:bisphenol A; D000098826:Bisphenol A Compounds