title: Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A.
abstract: Hypothalamic neurons, which produce the kisspeptin family of peptide hormones (Kp), are critical for initiating puberty and maintaining estrous cyclicity by stimulating gonadotropin-releasing hormone (GnRH) release. Conversely, RFamide-related peptide-3 (RFRP3) neurons inhibit GnRH activity. It has previously been shown that neonatal exposure to bisphenol A (BPA) can alter the timing of female pubertal onset and induce irregular estrous cycles or premature anestrus. Here we tested the hypothesis that disrupted ontogeny of RFamide signaling pathways may be a mechanism underlying advanced puberty. To test this, we used a transgenic strain of Wistar rats whose GnRH neurons express enhanced green fluorescent protein. Pups were exposed by daily subcutaneous injection to vehicle, 17beta-estradiol (E2), 50 μg/kg BPA, or 50 mg/kg BPA, from Postnatal Day (PND) 0 through PND 3, and then cohorts were euthanized on PNDs 17, 21, 24, 28, and 33 (5-8 animals per age per exposure; males were collected on PNDs 21 and 33). Vaginal opening was advanced by E2 and 50 μg/kg BPA. On PND 28, females exposed to E2 and 50 μg/kg BPA had decreased RFRP-3 fiber density and contacts on GnRH neurons. RFRP3 perikarya were also decreased in females exposed to 50 μg/kg BPA. Data suggest that BPA-induced premature puberty results from decreased inhibition of GnRH neurons.
authors.affiliation: Department of Biology, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Losa-Ward
authors.forename: Karina L
authors.initials: KL
authors.lastname: Todd
authors.forename: Katherine A
authors.initials: KA
authors.lastname: McCaffrey
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tsutsui
authors.forename: Heather B
authors.initials: HB
authors.lastname: Patisaul
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D001835:Body Weight / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects*; D059648:Kisspeptins / Q000378:metabolism*; D008297:Male; D009479:Neuropeptides / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D011629:Puberty, Precocious / Q000097:blood / Q000139:chemically induced*; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D014621:Vagina / Q000187:drug effects; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004968:Estrogens, Non-Steroidal; D007987:Gonadotropin-Releasing Hormone; D059648:Kisspeptins; D009479:Neuropeptides; D010636:Phenols; C416987:RFamide peptide; C006780:bisphenol A; D000098826:Bisphenol A Compounds