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The mechanisms of BPA exposure and in the developing mammary gland

Hindman, Andrea R
http://orcid.org/0000-0002-0275-3028
http://rave.ohiolink.edu/etdc/view?acc_num=osu1503321233777122

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
It is estimated that greater than 40,000 women in the United States will die from breast cancer this year and over 250,000 will be newly diagnosed. Greater than 70% of these cases are attributable to environmental factors, some of which are suspected to be a consequence of extensive human exposure to estrogenic compounds, collectively known as endocrine disrupting compounds (EDCs). Significant evidence from animal models suggests that chronic and/ or early-life exposure to known EDCs, such as bisphenol A (BPA) and genistein (GEN) are linked to increased risk and mediators of epithelial transformation to impart later-life development of breast cancer. However, the consequences of vast human exposures are largely unknown, immeasurable and the molecular mechanisms are largely undefined. Herein, we have utilized two distinct models to address undefined facets of the EDC mechanism. We address molecular mechanisms of chronic exposures that are representative of observed human exposures and examine windows of differential in utero BPA exposure to narrow possible developmental mechanisms at time of exposure that may propagate EDC-mediated alterations to later-life. We emphasize the importance of understanding the transcriptional alterations and epigenetic landscape of adult mammary component cell types, given the primary focus of current work to be on embryonic manifestation of disease and susceptibility. Our analyses demonstrate sustained reprogramming of the estrogen response beyond cessation of chronic exposures. Further we attribute the well-characterized BPA in utero phenotype to iii a period in mammary gland development corresponding to discrete tissue compartment interactions, corroborating the vital paracrine signaling that occurs at this in utero time of exposure. Our analyses are the first of its kind to map transcriptional and epigenetic alterations following in utero BPA exposure in the adult mammary gland. Taken together, our findings can inform analysis of human populations, determining the mechanisms of deregulation by in utero BPA exposures that contribute to later-life breast cancer risk and encourage alternative compounds. We believe while these mechanisms have been investigated specific to BPA, our findings can be extended to and provide a basis of concern for other known and suspected EDCs.
Craig Burd (Advisor)
Helen Chamberlin (Committee Member)
Ruth Keri (Committee Member)
Thomas Ludwig (Committee Member)
Mark Parthun (Committee Member)
178 p.
Biology; Biomedical Research; Developmental Biology; Endocrinology; Environmental Health; Epidemiology; Experiments; Food Science; Health; Histology; Molecular Biology; Morphology; Plastics; Public Health; Toxicology
Endocrine disruption, endocrine disrupting compounds, EDCs, chronic, breast cancer, estrogen, estrogen receptor, bisphenol A, BPA, genistein, microarray, histones, in utero, development, epigenetic, RNA-seq, ChIP, methylation, extracellular matrix

Recommended Citations

Citations

  • Hindman, A. R. (2017). The mechanisms of BPA exposure and in the developing mammary gland [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1503321233777122

    APA Style (7th edition)

  • Hindman, Andrea. The mechanisms of BPA exposure and in the developing mammary gland. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1503321233777122.

    MLA Style (8th edition)

  • Hindman, Andrea. "The mechanisms of BPA exposure and in the developing mammary gland." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1503321233777122

    Chicago Manual of Style (17th edition)

osu1503321233777122
557
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This open access ETD is published by The Ohio State University and OhioLINK.