Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A

Biol Reprod. 2012 Aug 2;87(2):28. doi: 10.1095/biolreprod.112.100826. Print 2012 Aug.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzhydryl Compounds
  • Body Weight / drug effects
  • Estrogens, Non-Steroidal / toxicity*
  • Female
  • Gonadotropin-Releasing Hormone / metabolism
  • Hypothalamus / drug effects*
  • Kisspeptins / metabolism*
  • Male
  • Neuropeptides / metabolism*
  • Phenols / toxicity*
  • Puberty, Precocious / blood
  • Puberty, Precocious / chemically induced*
  • Rats
  • Rats, Transgenic
  • Rats, Wistar
  • Vagina / drug effects

Substances

  • Benzhydryl Compounds
  • Estrogens, Non-Steroidal
  • Kisspeptins
  • Neuropeptides
  • Phenols
  • RFamide peptide
  • Gonadotropin-Releasing Hormone
  • bisphenol A