Academic journal article Environmental Health Perspectives

Neonatal Exposure to Bisphenol A Alters Reproductive Parameters and Gonadotropin Releasing Hormone Signaling in Female Rats

Academic journal article Environmental Health Perspectives

Neonatal Exposure to Bisphenol A Alters Reproductive Parameters and Gonadotropin Releasing Hormone Signaling in Female Rats

Article excerpt

BACKGROUND: Bisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins, and polystyrene and is found in many products. Several reports have reveal potent in vivo effects, because BPA acts as an estrogen agonist and/or antagonist and as an androgen and thyroid hormone antagonist.

OBJECTIVES: We analyzed the effects of neonatal exposure to BPA on the reproductive axis of female Sprague-Dawley rats.

METHODS: Female rats were injected subcutaneusly, daily, from postnatal day 1 (PND1) to PND10 with PBA [500 [micro]g/50 [micro]L (high) or 50 [micro]g/50 [micro]L (low)] in castor oil vehicle alone. We studied body weight and age at vaginal opening, estrous cycles, and pituitary hormone release in vivo and in vitro, as well as gonadotropin-releasing hormone (GnRH) pulsatility at PND13 and in adults. We also analyzed two GnRH-activated signaling pathways in the adults: inositol-triphosphate ([IP.sub.3]), and extracellular signal-regulated kinase [.sub.1/2.([ERK.sub.1/2])].

RESULTS: Exposure to BPA altered pituitary function in infantile rats, lowering basal and GnRH-induced luteinizing hormone (LH) and increasing GnRH pulsatility. BPA dose-dependently accelerated puberty onset and altered estrous cyclicity, with the high dose causing permanent estrus. In adults treated neonatally with BPA, GnRH-induced LH secretion in vivo was decreased and GnRH pulsatility remained disrupted. In vitro, pituitary cells from animals treated with BPA showed lower basal LH anad dose-dependently affected GnRH-induced [IP.sub.3] formation; the high dose also impaired GnRH-induced Lh-section. Both doses altered [ERI.K.sub.1/2] activation.

CONCLUSIONS: Neonatal exposure to BPA altered reproductive parametees and hypothalamic pituitary function in female rats. To our knowledge, these results demonstrate of the first time that neonatal in vivo BPA permanently affected GnRH pulsatility and pituitary GnRH signaling.

KEY WORDS: Bisphenol, A, estrous cycle, GnRH pulsatility, GnRH, signaling, gonadotropins, puberty. Environ Health Perspect 117:757 (2009). doi: 10.1289/ehp.0800267 available via[Online 7] January 2009


Humans and wildlife are exposed to a variety of contaminants, such as xenoestrogens, on a daily basis. Bisphenol A (BPA), a xenoestrogen, is a constituent of polycarbonate plastics and epoxy resins used in dentistry and in the food industry. The polymer bonds hydrolyze at high temperatures and release BPA. BPA could be ingested by humans; detectable amounts have been found in food cans, microwave containers, polycarbonate bottles, and in human saliva after treatment with dental sealants (Vandenberg et al. 2007). Although results of some in vitro assays have suggested that BPA is a weak environmental estrogen (Vandenberg et al. 2007; Wetherill et al. 2007), important in vivo effects have been found using a wide range of doses, animal models, and study end points. The current U.S. Environmental Protection Agency (EPA) reference dose [50 [micro]g/kg/day (U.S. EPA 1993)] was calculated by dividing the lowest observed adverse effect level (LOAEL; 50 mg/kg/day) by 1,000. For the present study, we defined low doses as those < LOAEL, as reported by Richter et al. (2007). Effects of BPA can be influenced by species, strain, dose, and time of exposure. Adult animals exposed to BPA show effects that are reversible when the exposure ceases (Richter et al. 2007). In contrast, perinatal or neonatal exposure produces organizational effects that are irreversible in Sprague-Dawley (Kato et al. 2003; Moral et al. 2008; Patisaul et al. 2006; Rubin et al. 2001), Wistar (Durando et al. 2007; Ramos et al. 2003), and Fisher 344 rats (Khurana et al. 2000). These permanent effects are in agreement with the actions of estrogens during development, ranging from the establishment of sex differences to pervasive trophic and neuroprotective effects (McCarthy 2008). …

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