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Marina Fernández,^1,2 Maria Bianchi,¹ Victoria Lux-Lantos,¹ and Carlos Libertun^1,2

¹Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; ²Facultad de Medicina, Universidad de Buenos Aires, Argentina

Abstract
Background: Bisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins, and polystyrene and is found in many products. Several reports have revealed 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 BPA [500 µg/50 µL (high) or 50 µg/50 µL (low) ] in castor oil or with 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 (IP₃) , and extracellular signal-regulated kinase _1/2 (ERK_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 and dose-dependently affected GnRH-induced IP₃ formation ; the high dose also impaired GnRH-induced LH secretion. Both doses altered ERK_1/2 activation.

Conclusions: Neonatal exposure to BPA altered reproductive parameters and hypothalamic–pituitary function in female rats. To our knowledge, these results demonstrate for the first time that neonatal in vivo BPA permanently affects GnRH pulsatility and pituitary GnRH signaling.

Key words: Bisphenol A, estrous cycle, GnRH pulsatility, GnRH signaling, gonadotropins, puberty. Environ Health Perspect 117:757–762 (2009) . doi:10.1289/ehp.0800267 available via http://dx.doi.org/ [Online 7 January 2009]

Address correspondence to C. Libertun, IByME-CONICET, Vuelta de Obligado 2490, (C1428ADN) Buenos Aires, Argentina. Telephone: 54-11-4783-2869. Fax: 54-11-4786-2564. E-mail: libertun@dna.uba.ar

This research was supported by Consejo Nacional de Investigaciones Científicas y Técnicas, Agencia Nacional de Promoción Científica y Tecnológica (BID 1728/OC-AR PICT 2004 05–26307 to C.L. and PICT 2006 N° 00200 to V.L.L.) and Universidad de Buenos Aires (ME 048 and 038) .

The authors declare they have no competing financial interests.

Received 8 October 2008 ; accepted 6 January 2009.