Research Prenatal Bisphenol A Exposure Induces Preneoplastic Lesions in the Mammary Gland in Wistar Rats (original) (raw)
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Prenatal Bisphenol A Exposure Induces Preneoplastic Lesions in the Mammary Gland in Wistar Rats
Environmental Health Perspectives, 2006
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-Nmethylurea (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).
Perinatally Administered Bisphenol A as a Potential Mammary Gland Carcinogen in Rats
Environmental Health Perspectives, 2013
Background: Environmental exposure to bisphenol A (BPA) affects mammary gland development in rodents and primates. Prenatal exposure to environmentally relevant doses of BPA increased the number of intraductal hyperplasias and ductal carcinomas in situ by 50 days of age in Wistar-Furth rats. oBjective: We aimed to determine whether BPA exposure of dams during gestation only or throughout lactation affects the incidence of mammary gland neoplasia in female offspring. Methods: We treated pregnant Sprague-Dawley rats with BPA at 0, 0.25, 2.5, 25, or 250 μg BPA/kg BW/day from gestational day (GD) 9 to birth and from GD9 to postnatal day (PND) 21. Mammary glands from BPA-exposed offspring were examined at four time points for pre neoplastic and neo plastic lesions. To assess circulating BPA levels, we exposed pregnant rats to vehicle or 250 μg BPA/kg BW/day during gestation only or during gestation/lactation and analyzed sera from dams, fetuses, and nursing pups for total and unconjugated BPA. results: Total and unconjugated BPA were detected in sera from 100% of dams and fetuses and 33% of pups exposed to 250 μg BPA/kg BW/day. Unconjugated BPA levels in exposed dams and fetuses (gestational) and in exposed dams and pups (gestational/lactational) were within levels found in humans. Preneoplastic lesions developed in BPA-exposed female offspring across all doses as early as PND50. Unexpectedly, mammary gland adenocarcinomas developed in BPA-exposed offspring by PND90. conclusions: Our findings suggest that developmental exposure to environmentally relevant levels of BPA during gestation and lactation induces mammary gland neoplasms in the absence of any additional carcinogenic treatment. Thus, BPA may act as a complete mammary gland carcinogen.
Biology of reproduction, 2001
Exposure to estrogens throughout a woman's life, including the period of intrauterine development, is a risk factor for the development of breast cancer. The increased incidence of breast cancer noted during the last 50 years may have been caused, in part, by exposure of women to estrogen-mimicking chemicals that are released into the environment. Here, we investigated the effects of fetal exposure to one such chemical, bisphenol A (BPA), on development of the mammary gland. CD-1 mice were exposed in utero to low, presumably environmentally relevant doses of BPA (25 and 250 microg/kg body weight), and their mammary glands were assessed at 10 days, 1 mo, and 6 mo of age. Mammary glands of BPA-exposed mice showed differences in the rate of ductal migration into the stroma at 1 mo of age and a significant increase in the percentage of ducts, terminal ducts, terminal end buds, and alveolar buds at 6 mo of age. The percentage of cells that incorporated BrdU was significantly decrease...
Oral Exposure to Bisphenol A Increases Dimethylbenzanthracene-Induced Mammary Cancer in Rats
Environmental Health Perspectives, 2009
Background: Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles. oBjectives: Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer. methods: We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 µg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age. results: The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days post partum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1-3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age. conclusions: The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1-3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure. key words: apoptosis, bisphenol A, mammary cancer, proliferation, steroid receptor coactivators. Environ Health Perspect 117:910-915 (2009). doi:10.1289/ehp.11751 available via http://dx.doi. org/ [Online 7 January 2009]
Molecular Endocrinology, 2011
Bisphenol A [BPA, propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor B ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer. (Molecular Endocrinology 25: 0000 -0000, 2011) NURSA Molecule Pages † : Nuclear Receptors: PR; Ligands: Bisphenol A.
Reproductive Toxicology, 2007
Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast cancer during adult life. Fetal exposure to low doses of the xenoestrogen bisphenol A resulted in long-lasting effects in the mouse mammary gland that were manifested during adult life. It enhanced sensitivity to estradiol, decreased apoptosis, increased the number of progesterone receptor-positive epithelial cells at puberty and increased lateral branching at 4 months of age. We now report that fetal exposure to 2.5, 25, 250 and 1000μg bisphenol A/kg body weight/day induces the development of ductal hyperplasias and carcinoma in situ at postnatal day 50 and 95 in rats. These highly proliferative lesions have an increased number of estrogen receptor-α positive cells. Thus, fetal bisphenol A exposure is sufficient to induce the development of preneoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumor development.
Endocrinology, 2006
Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials, food and beverage containers, and other plastic consumer products. Effects of perinatal BPA exposure on the mouse mammary gland have been observed in puberty and adulthood, long after the period of exposure has ended. The aim of this study was to examine fetal mammary gland development at embryonic day (E)18 and assess changes in the tissue organization and histoarchitecture after exposure to an environmentally relevant dose of BPA. In unexposed fetuses, the relative position of the fetus with respect to its female and male siblings in the uterus influenced growth of the ductal tree, which was more developed in females placed between two males than in females placed between two females. Exposure of dams to 250 ng BPA per kilogram body weight per day from E8 to E18 significantly increased ductal area and ductal extension in exposed fetuses and obliterated positional differences. In the stroma, BPA exposure promoted maturation of the fat pad and altered the localization of collagen. Within the epithelium, BPA exposure led to a decrease in cell size and delayed lumen formation. Because mammary gland development is dependent on reciprocal interactions between these compartments, the advanced maturation of the fat pad and changes in the extracellular matrix may be responsible for the altered growth, cell size, and lumen formation observed in the epithelium. These results suggest that alterations in mammary gland phenotypes observed at puberty and adulthood in perinatally exposed mice have their origins in fetal development.
Journal of Endocrinology, 2008
Bisphenol A (BPA), known as an environmental endocrine disruptor, is widely used as a plasticizer. This study aims to investigate whether exposure in utero to BPA alters the architecture, proliferative index, and genomic signature of the rat mammary gland during critical stages of development. Pregnant rats were gavaged with 25 mg BPA/kg body weight (BW; low-dose group) or 250 mg BPA/kg BW (high-dose group) from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50, and 100 days, and mammary glands were collected. Analysis of gland morphology was performed from whole-mounted mammary tissue, while proliferative index was determined by detection of bromodeoxyuridine incorporation in the epithelial cells. Genomic profiles were obtained by microarray analysis, and some genes were validated by real-time RT-PCR. BPA exposure induced changes in the mammary gland that were time and dose specific. High-dose exposure resulted in architectural modifications, mainly in the number of undifferentiated epithelial structures of the breast tissue. Proliferative index did not show remarkable differences by the effect of BPA. Low and high doses of BPA changed the gene expression signature of the mammary gland following a different fashion: low dose had the highest effect by 50 days, while high dose had a highest influence on gene expression by 100 days. Both doses presented a significant cluster of up-modulated genes related to the immune system at the age of maximal changes. Moreover, high-dose exposure induced changes in genes related to differentiation suggesting alterations in the normal development of the gland. The increase of undifferentiated structures and the changes in the gene expression profile at different ages suggest that prenatal exposure to BPA can affect the susceptibility of the mammary gland to transformation.
Biology of Reproduction, 2001
Exposure to estrogens throughout a woman's life, including the period of intrauterine development, is a risk factor for the development of breast cancer. The increased incidence of breast cancer noted during the last 50 years may have been caused, in part, by exposure of women to estrogen-mimicking chemicals that are released into the environment. Here, we investigated the effects of fetal exposure to one such chemical, bisphenol A (BPA), on development of the mammary gland. CD-1 mice were exposed in utero to low, presumably environmentally relevant doses of BPA (25 and 250 g/kg body weight), and their mammary glands were assessed at 10 days, 1 mo, and 6 mo of age. Mammary glands of BPA-exposed mice showed differences in the rate of ductal migration into the stroma at 1 mo of age and a significant increase in the percentage of ducts, terminal ducts, terminal end buds, and alveolar buds at 6 mo of age. The percentage of cells that incorporated BrdU was significantly decreased within the epithelium at 10 days of age and increased within the stroma at 6 mo of age. These changes in histoarchitecture, coupled with an increased presence of secretory product within alveoli, resemble those of early pregnancy, and they suggest a disruption of the hypothalamic-pituitary-ovarian axis and/or misexpression of developmental genes. The altered relationship in DNA synthesis between the epithelium and stroma and the increase in terminal ducts and terminal end buds are striking, because these changes are associated with carcinogenesis in both rodents and humans.