Prenatal Bisphenol A Exposure Induces Preneoplastic Lesions in the Mammary Gland in Wistar Rats

Laboratorio de Endocrinologia y Tumores Hormonodependientes, School of Biochemistry and Biological Sciences, Universidad Nacional del Litoral, Santa Fe, Argentina.
Environmental Health Perspectives (Impact Factor: 7.98). 02/2007; 115(1):80-6. DOI: 10.1289/ehp.9282
Source: PubMed


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.
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).
Pregnant Wistar rats were exposed to BPA (25 pg/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.
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.
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.

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    • "Long-term exposure to food additives, including nitrite preservatives and artificial azo-dyes may be also involved in chemically-induced carcinogenesis, due to their mutagenic properties (Palmer and Mathews, 1986; Weisburger, 1986; Sasaki et al., 2002 ). In addition, Bisphenol A, a xenoestrogen used in plastic food containers, because it can migrate in food and be repetitively ingested, has been recently suspected to be carcinogenic in humans on the basis of results obtained from animal studies aiming at reproducing breast (Durando et al., 2007) and prostate cancer genesis (Ho et al., 2006; Prins et al., 2007). This led to the hypothesis that in association with individual diet and nutrition lifestyle-related factors, chronic exposure to food contaminants and food additives might be involved in carcinogenesis more frequently than it is usually appreciated . "

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    • "BPA is well known as an endocrine disrupting chemical (EDC) and its adverse effect on reproduction has been well documented. In rodents, perinatal exposure to environmentally relevant levels of BPA decreased fertility and fecundity in CD-1 mice (Cabaton et al., 2011), induced female offspring earlier vaginal opening and exhibited advanced puberty (Durando et al., 2007), decreased the anogenital distance of male offspring (Miao et al., 2011), and decreased embryo implantation rate (Berger and Foster, 2010). In the terrestrial isopod Porcellio, BPA exposure elicited reproductive toxicity by decreasing female reproductive allocation and increased abortions rate (Lemos et al., 2010). "
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    • "Decreased tumor latency, increased tumor multiplicity, tumor burden and metastasis (Jenkins et al. 2011) Mammary Mice/ FVB/N 2 -250µg/kg/day Oral E8 to parturition DMBA Decreased tumor latency and increased tumor susceptibility (Weber Lozada et al. 2011) Mammary Mice/C57BL/6 0.6µg -1.2mg/kg/day Oral E1 to PND24 -- Increased number of TEB and PR expressing mammary epithelial cells (Ayyanan et al. 2011) Mammary Rats/SD 25-250µg/kg/day Oral PND2 to PND21 and E2 to E20 DMBA Decreased tumor latency, and increased number of mammary tumors. (Lamartiniere et al.2011) Mammary Mice/CD-1 5mg/kg/day IP E9 to parturition -- No effect on EZH2 mRNA expression, increased EZH2 protein expression and activity (Doherty et al. 2010) Mammary Rats/SD 25-250 µg/kg/day Oral E10 to E21 DMBA Decreased tumor latency and increased tumor susceptibility (Betancourt et al. 2010) Mammary Rats/SD 25-250 µg/kg day Oral PND2 -PND20 DMBA Decreased tumor latency and increase in mammary tumor formation (Jenkins et al. 2009) Mammary Rats/SD 25-250µg/kg/day Oral E10 to parturition -- Increased number of TEBs, TDs, and lobular structures during development (Moral et al. 2008) Mammary Rats/Wistar 25µg/kg/day Osmotic pump E8 to E23 NMU Increase in ductal hyperplasia formation (Durando et al. 2007) "
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    ABSTRACT: The estrogenic properties of bisphenol A (BPA), a ubiquitous synthetic monomer that can leach into the food and water supply, have prompted considerable research into exposure-associated health risks in humans. Endocrine-disrupting properties of BPA suggest it may impact developmental plasticity during early life, predisposing individuals to disease at doses below the oral reference dose (RfD) established by the Environmental Protection Agency in 1982. Herein, we review the current in vivo literature evaluating the carcinogenic properties of BPA. We conclude that there is substantial evidence from rodent studies indicating that early-life BPA exposures below the RfD lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of "carcinogen" put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumor promoting properties.
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