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Milena Durando,¹ Laura Kass,¹ Julio Piva,¹ Carlos Sonnenschein,² Ana M. Soto,² Enrique H. Luque,¹ and Mónica Muñoz-de-Toro¹

¹Laboratorio de Endocrinología y Tumores Hormonodependientes, School of Biochemistry and Biological Sciences, Universidad Nacional del Litoral, Santa Fe, Argentina; ²Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts, USA

Abstract
Background: Humans are routinely exposed to bisphenol A (BPA) , an estrogenic compound that leaches from dental materials, food and beverage containers, and other consumer products. Prenatal exposure to BPA has produced long-lasting and profound effects on rodent hormone-dependent tissues that are manifested 1–6 months after the end of exposure.

Objective: The aim of the present work was to examine whether in utero exposure to BPA alters mammary gland development and increases its susceptibility to the carcinogen N-nitroso-N-methylurea (NMU) .

Methods: Pregnant Wistar rats were exposed to BPA (25 µg/kg body weight per day) or to vehicle. Female offspring were sacrificed on postnatal day (PND) 30, 50, 110, or 180. On PND50 a group of rats received a single subcarcinogenic dose of NMU (25 mg/kg) and they were sacrificed on either PND110 or PND180.

Results: At puberty, animals exposed prenatally to BPA showed an increased proliferation/apoptosis ratio in both the epithelial and stromal compartments. During adulthood (PND110 and PND180) , BPA-exposed animals showed an increased number of hyperplastic ducts and augmented stromal nuclear density. Moreover, the stroma associated with hyperplastic ducts showed signs of desmoplasia and contained an increased number of mast cells, suggesting a heightened risk of neoplastic transformation. Administration of a subcarcinogenic dose of NMU to animals exposed prenatally to BPA increased the percentage of hyperplastic ducts and induced the development of neoplastic lesions.

Conclusions: Our results demonstrate that the prenatal exposure to low doses of BPA perturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to a chemical challenge administered 50 days after the end of BPA exposure.

Key words: bisphenol A (BPA) , desmoplasia, endocrine disruptor, hyperplastic ducts, mammary tumor, mast cells, N-nitroso-N-methylurea (NMU) . Environ Health Perspect 115: 80–86 (2007) . doi:10.1289/ehp.9282 available via http://dx.doi.org/ [Online 29 August 2006]

Address correspondence to M. Muñoz-de-Toro, Laboratorio de Endocrinología y Tumores Hormonodependientes, School of Biochemistry and Biological Sciences, Casilla de Correo 242, (3000) Santa Fe, Argentina. Telephone/Fax: 54-342-4575207. E-mail: monicamt@fbcb.unl.edu.ar

This work was supported by grants from the Universidad Nacional del Litoral (CAI+D program) , the Argentine National Agency for the Promotion of Science and Technology (ANPCyT) , and the National Institutes of Health (ES08314 and ES012301) . M.D. is a fellow, and L.K. and E.H.L. are career investigators of the Argentine National Council for Science and Technology (CONICET) .

The authors declare they have no competing financial interests.

Received 21 April 2006 ; accepted 29 August 2006.