: Endocrine disrupters are thought to be an underlying risk factor for the high incidence of hormone related diseases such as early puberty onset and breast cancer. Estrogens play a central role both in the onset of puberty and the etiology of breast cancer. Because estrogen receptor-alpha (ER-a) mediates many of the effects of estrogens, molecules that can bind to and activate ER-a can potentially advance the onset of puberty and increase the risk of breast cancer. Published studies from this laboratory demonstrate that the metalloid arsenite activates ER-a through a high affinity interaction (KI = 10-10 M) with hormone binding domain of the receptor involving amino acids C381, C447, H524, K529 and/or K531, and N532. More importantly, it has been shown that an environmentally relevant dose of arsenite mimics the effects of estradiol on the growth and expression of genes in MCF-7 breast cancer cells. Preliminary data presented in this application demonstrate that environmentally relevant doses of arsenite also mimic the effects of estrogens in vivo. In ovariectomized animals, arsenite increases uterine wet weight and induces estrogen regulated genes. In intact animals, prepubertal exposure to arsenite accelerates the development of the mammary gland and increases the incidence of mammary tumors in animals challenged with the chemical carcinogen dimethylbenzanthracene, consistent with an estrogen like effect on mammary tumorigenesis. Based on these observations, this application will test the hypothesis that early life exposure to environmentally relevant amounts of arsenite imprints or reprograms gene expression in the mammary gland leading to early onset of puberty and increased susceptibility to mammary tumorigenesis.
Specific Aim 1 will identify genes altered by prepubertal exposure to arsenite and determine whether their expression is altered through epigenetic mechanisms.
Specific Aim 2 will determine whether in utero exposure to arsenite alters gene expression. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES015160-01
Application #
7171965
Study Section
Special Emphasis Panel (ZES1-LWJ-E (EP))
Program Officer
Tyson, Frederick L
Project Start
2006-09-25
Project End
2008-06-30
Budget Start
2006-09-25
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$232,800
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Parodi, Daniela A; Greenfield, Morgan; Evans, Claire et al. (2017) Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium. Int J Mol Sci 18:
Parodi, Daniela A; Greenfield, Morgan; Evans, Claire et al. (2015) Alteration of mammary gland development and gene expression by in utero exposure to arsenic. Reprod Toxicol 54:66-75