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.


Available from: Laura Kass
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bisphenol A (BPA), a high-volume chemical used to make polycarbonate plastic and epoxy resins, is a ubiquitous contaminant in environment and human body. To investigate the reproductive effects of long-term exposure to low concentrations of BPA, a two-generation study was conducted using the aquatic model species of zebrafish. Our findings revealed that exposure to 1nM (0.228μg/L) BPA for continuous two generations resulted in female-biased sex ratio in both F1 and F2 adult population, decreased sperm density, and decreased sperm quality as measured by motility, velocity, ATP content and lipid peroxidation in F1 and F2 males. Females were less sensitive to BPA exposures than males as no adverse effects were found in female gonads or gametes. Delayed hatching at 48hpf and increased malformation and mortality were found in the offspring from BPA exposed F2, but not F1 parents. Most importantly, the adverse effect on larval development and survival from BPA exposed F2 parents was paternal-specific, resulting mainly from BPA exposed males. Subsequent transcription analysis of F2 male gonads revealed dysregulated mitochondrial biogenesis and significant activation of non-canonical Wnt/planar cell polarity and Wnt/Calcium signaling pathways. Gene expression analysis of larvae from BPA exposed F2 parents showed significant reduced expression of DNA methyltransferases such as dnmt1, dnmt3, and dnmt5. In conclusion, low level BPA exposures for continuous two generations not only affects sex ratio and sperm quantity/quality in F1 and F2 adults, reproductive success in offspring from F2 parents, but also perturbs various molecular pathways potentially contributing to these BPA induced male-specific reproductive defects.
    Aquatic toxicology (Amsterdam, Netherlands) 11/2015; 169:204-214. DOI:10.1016/j.aquatox.2015.10.020 · 3.45 Impact Factor
  • Source
    • "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) "
    [Show abstract] [Hide abstract]
    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.
    Reproductive Toxicology 10/2015; DOI:10.1016/j.reprotox.2015.09.006 · 3.23 Impact Factor
  • Source
    • "To date, these studies examining effects of BPA on tumorigenesis have focused on the reproductive tract and mammary glands. rats exposed prenatally to greater doses of BPA-induced in situ development of carcinomas (Durando et al. 2007). exposure to BPA during nursing followed by exposure at 50 days of age to dimethylbenzantracene resulted in more of tumors per rat and a shorter latency period compared with animals not exposed to BPA (Jenkins et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: More and more evidences indicate that endocrine disruptor chemicals such as bisphenol A (BPA) can act as carcinogens and enhance susceptibility to tumorigenesis. Although the gut is in direct contact with orally ingested BPA, effects of BPA on occurrence and development of colorectal cancer remain an unexplored endpoint. Colorectal cancer SW480 cells treated with nanomolar (10(-8) M) or greater (10(-5) M) concentrations of BPA were compared with responses of a control group. Proteomic study revealed that more than 56 proteins were modulated following exposure to BPA, which are relevant to structure, motility and proliferation of cells, production of ATP, oxidative stress, and protein metabolism. Further studies revealed that BPA increased migration and invasion and triggered transformations from epithelial to mesenchymal transitions (EMTs) of colorectal cancer cells, which was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin with a concomitant decrease of E-cadherin. Accordingly, BPA treatment increased the expression of transcription factor Snail. Furthermore, signal AKT/GSK-3β-mediated stabilization of Snail is involved during BPA-induced EMT of colon cancer cells. Our study first demonstrated that the xenoestrogen BPA at nanomolar and greater concentrations modulates the protein profiles and promotes the metastasis of colorectal cancer cells via induction of EMT.
    Archive für Toxikologie 08/2014; 89(8). DOI:10.1007/s00204-014-1301-z · 5.98 Impact Factor
Show more