Developmental exposure to bisphenol-A (BPA) at doses within the range of human exposure causes a complex array of adverse effects in animals. These outcomes are also known to be present in human populations and the rise in their occurrence coincides with the massive use of BPA and other endocrine disrupting chemicals in consumer goods. The main hormonal activity of BPA is as an estrogen mimic. Exposure to estrogens throughout a woman's life, including the period of fetal development, is considered a main risk factor for breast cancer. Developmental exposure to BPA altered mammary gland morphogenesis in rodents during the period of exposure and led to the development of pre-neoplastic and neoplastic lesions appearing in adulthood. The goal of this proposal is to identify the molecular, cellular and morphogenetic mechanisms underlying BPA-driven altered mammogenesis that predisposes to neoplastic transformation. To achieve this goal, we will use innovative tools such as a fetal mammary gland explant culture model that allows testing for direct effects of hormones and real-time observation of organogenesis.
The Specific Aims of this proposal are to test three hypotheses, namely, 1: that the direct effect BPA on mammary gland development is mediated by ER1 and/or 2. 2: that BPA causes altered ductal morphogenesis i) by altering the composition and physical properties of the ECM and ii) by inducing adipogenesis. 3: that the different mammary gland phenotypes resulting from gestational and gestational plus lactational BPA exposure are due to alterations at the hypothalamic level.

Public Health Relevance

Perinatal exposure to xenoestrogens, such as BPA, induce deleterious health effects such as obesity, infertility and mammary neoplasias in rodents. During the last fifty years, the prevalence of these pathologies also increased in human populations, suggesting a link between BPA exposure and these outcomes. We observed that animals exposed perinatally to low doses of BPA developed mammary precancerous lesions. The proposed study aims at characterizing the mechanisms underlying this effect. This is of utmost relevance to the evaluation of BPA, a widespread contaminant found in 92% of the tested American population, and therefore it has the potential to greatly impact public health and public health policy. Additionally, this research promises to develop a method to assess the potential breast carcinogenicity of other toxicants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008314-17
Application #
8473213
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (02))
Program Officer
Heindel, Jerrold
Project Start
1996-09-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
17
Fiscal Year
2013
Total Cost
$582,463
Indirect Cost
$203,044
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Sweeney, Michael F; Sonnenschein, Carlos; Soto, Ana M (2018) Characterization of MCF-12A cell phenotype, response to estrogens, and growth in 3D. Cancer Cell Int 18:43
Liu, Zhiyi; Speroni, Lucia; Quinn, Kyle P et al. (2018) 3D organizational mapping of collagen fibers elucidates matrix remodeling in a hormone-sensitive 3D breast tissue model. Biomaterials 179:96-108
Sonnenschein, Carlos; Soto, Ana M (2018) An Integrative Approach Toward Biology, Organisms, and Cancer. Methods Mol Biol 1702:15-26
Acevedo, Nicole; Rubin, Beverly S; Schaeberle, Cheryl M et al. (2018) Perinatal BPA exposure and reproductive axis function in CD-1 mice. Reprod Toxicol 79:39-46
Soto, Ana M; Sonnenschein, Carlos (2018) Endocrine disruptors - putting the mechanistic cart before the phenomenological horse. Nat Rev Endocrinol 14:317-318
Rubin, Beverly S; Paranjpe, Maneesha; DaFonte, Tracey et al. (2017) Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates adverse effects in female mice. Reprod Toxicol 68:130-144
Speroni, Lucia; Voutilainen, Maria; Mikkola, Marja L et al. (2017) New insights into fetal mammary gland morphogenesis: differential effects of natural and environmental estrogens. Sci Rep 7:40806
Paulose, Tessie; Montévil, Maël; Speroni, Lucia et al. (2016) SAMA: A Method for 3D Morphological Analysis. PLoS One 11:e0153022
Sonnenschein, Carlos; Soto, Ana M (2016) Carcinogenesis explained within the context of a theory of organisms. Prog Biophys Mol Biol 122:70-76
Montévil, Maël; Speroni, Lucia; Sonnenschein, Carlos et al. (2016) Modeling mammary organogenesis from biological first principles: Cells and their physical constraints. Prog Biophys Mol Biol 122:58-69

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