Breast cancer (BC) is a hormone-dependent malignancy. Endocrine disrupters (EDs) are exogenous substances with hormonal activity in the endocrine system that disrupts the physiologic function of endogenous hormones. Animal studies unequivocally demonstrated that EDs disrupt development of mammary tissues and increase the risk of mammary tumors depending upon the dose and timing of exposure. However, evidence directly linking EDs and BC in human populations is far from conclusive. Two major issues have seriously limited translation of laboratory experiments into population studies. First, the window of susceptibility has not been clearly elucidated in humans. Second, most animal studies have tested one ED at a time often with doses orders of magnitude higher than common human exposure. Thus dose-extrapolations are usually performed neglecting possible synergistic or antagonist effects in a complex mixture of EDs that humans are more likely to encounter. Population studies of ED-BC associations are urgently needed that incorporate realistic exposure schemes and the concept of susceptibility windows. This proposed study uses an innovative approach of combining both an animal and a population study. First, animals will be exposed to three commonly-used EDs (individually and in combination) in physiological relevant doses at 6 different windows of development. Whole-genome expression and pathological features of rat mammary tissues will be profiled to provide both quantitative and qualitative biological effects of EDs. The investigators will then validate the laboratory findings in the population-based Long Island Breast Cancer Study Project (LIBCSP) through the use of its extensive database and biorepository. The overarching goal is to explore whether environmental EDs are acting in specific developmental windows and whether they exert their biological effects independently or synergistically/antagonistically in breast tissue leading to breast cancer development. Results from this study would provide invaluable information on effects of environmental exposure during women's life course, which may be used to direct future molecular epidemiological studies on ED exposure and BC. Should this study approach provide the information as expected, it will lead to the development of an animal model that can be used to study a wide range of EDs and other exogenous factors with significant implications for future investigations on the timing of environmental exposures to human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01ES019459-05S1
Application #
8914808
Study Section
Special Emphasis Panel (ZES1-LKB-V (02))
Program Officer
Reinlib, Leslie J
Project Start
2010-09-07
Project End
2015-08-30
Budget Start
2014-08-22
Budget End
2015-08-30
Support Year
5
Fiscal Year
2014
Total Cost
$169,500
Indirect Cost
$69,500
Name
Icahn School of Medicine at Mount Sinai
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Gopalakrishnan, Kalpana; Teitelbaum, Susan L; Lambertini, Luca et al. (2017) Changes in mammary histology and transcriptome profiles by low-dose exposure to environmental phenols at critical windows of development. Environ Res 152:233-243
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Hu, Jianzhong; Raikhel, Vincent; Gopalakrishnan, Kalpana et al. (2016) Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model. Microbiome 4:26
Manservisi, Fabiana; Gopalakrishnan, Kalpana; Tibaldi, Eva et al. (2015) Effect of maternal exposure to endocrine disrupting chemicals on reproduction and mammary gland development in female Sprague-Dawley rats. Reprod Toxicol 54:110-9
Teitelbaum, Susan L; Belpoggi, Fiorella; Reinlib, Les (2015) Advancing research on endocrine disrupting chemicals in breast cancer: Expert panel recommendations. Reprod Toxicol 54:141-7
White, Alexandra J; Teitelbaum, Susan L; Stellman, Steven D et al. (2014) Indoor air pollution exposure from use of indoor stoves and fireplaces in association with breast cancer: a case-control study. Environ Health 13:108

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