Exposure to Environmentally Relevant Doses of the Xenoestrogen Bisphenol-A Alters Development of the Fetal Mouse Mammary Gland (original) (raw)
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Reproductive Toxicology, 2008
Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from consumer products. Given the sensitivity of the developing organism to hormones, exposure of fetuses and infants is a concern. Here, CD-1 mice were exposed to environmentally relevant doses of BPA during gestation and the lactational period (gestational day 8 through postnatal day 16). At 3, 9 and 12-15 months of age, mammary glands from exposed offspring were examined for structural changes. BPA-exposed females demonstrated altered mammary phenotypes including the appearance of alveolar buds. Additionally, intraductal hyperplasias were observed exclusively in BPA-exposed females. These lesions had the appearance of "beaded" ducts, with epithelial cells present inside the ductal lumen and increased proliferation indexes compared to normal ducts. Similar structures have also been observed following exposure to other estrogens. These results are further evidence that perinatal BPA exposure can alter the morphology of the rodent mammary gland in adulthood. (A.M. Soto). older was significantly increased compared to unexposed women .
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...
Perinatal Exposure to Bisphenol-A Alters Peripubertal Mammary Gland Development in Mice
2010
Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of perinatal exposure to low, environmentally relevant doses of BPA [25 and 250 ng BPA/kg body weight (bw)·d] on the peripubertal development of the mammary gland. BPA exposure enhanced the mammary glands' sensitivity to estradiol in ovariectomized CD-1 mice. In their intact 30-d-old littermates, the area and numbers of terminal end buds relative to the gland ductal area increased whereas their apoptotic activity decreased. There was a positive correlation between ductal length and the age at first proestrus; that was reduced as the BPA dose increased, suggesting that BPA exposure slows down ductal invasion of the stroma. There was also a significant increase of progesterone receptor-positive ductal epithelial cells that were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in mice exposed to 25 ng BPA /kg bw·d. In conclusion, perinatal exposure to environmentally relevant BPA doses results in persistent alterations in mammary gland morphogenesis. Of special concern is the increased terminal end bud density at puberty as well as the increased number of terminal ends reported previously in adult animals, as these two structures are the sites at which cancer arises in humans and rodents.
Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer
Reproductive Toxicology, 2014
34 Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the 35 genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as 36 well as breast cancer later in life. Gestational exposure of rodents to a related compound, 37 the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary 38 cancer during adulthood, long after cessation of exposure. Exposure to BPA during 39 gestation induces morphological alterations in both the stroma and the epithelium of the 40 fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is 41 the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. 42 BPA would then alter the reciprocal stroma-epithelial interactions that mediate 43 mammogenesis. In addition to this direct effect on the mammary gland, BPA is 44 postulated to affect the hypothalamus and thus in turn affect the regulation of 45 mammotropic hormones at puberty and beyond. 46 47 Highlights: 4 Keywords: 59 fetal mammary gland, mammary gland development, xenoestrogens, endocrine 60
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.
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.
Bisphenol A alters the development of the rhesus monkey mammary gland
Proceedings of the National Academy of Sciences, 2012
The xenoestrogen bisphenol A (BPA) used in the manufacturing of various plastics and resins for food packaging and consumer products has been shown to produce numerous endocrine and developmental effects in rodents. Exposure to low doses of BPA during fetal mammary gland development resulted in significant alterations in the gland's morphology that varied from subtle ones observed during the exposure period to precancerous and cancerous lesions manifested in adulthood. This study assessed the effects of BPA on fetal mammary gland development in nonhuman primates. Pregnant rhesus monkeys were fed 400 μg of BPA per kg of body weight daily from gestational day 100 to term, which resulted in 0.68 ± 0.312 ng of unconjugated BPA per mL of maternal serum, a level comparable to that found in humans. At birth, the mammary glands of female offspring were removed for morphological analysis. Morphological parameters similar to those shown to be affected in rodents exposed prenatally to BPA were measured in whole-mounted glands; estrogen receptor (ER) α and β expression were assessed in paraffin sections. Student's t tests for equality of means were used to assess differences between exposed and unexposed groups. The density of mammary buds was significantly increased in BPA-exposed monkeys, and the overall development of their mammary gland was more advanced compared with unexposed monkeys. No significant differences were observed in ER expression. Altogether, gestational exposure to the estrogen-mimic BPA altered the developing mammary glands of female nonhuman primates in a comparable manner to that observed in rodents. endocrine disruptor | perinatal exposure | morphogenesis | internal dose | mammogenesis
2013
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 co...