The developing fetus is uniquely sensitive to long-term imprinting effects of estrogenic chemicals that are known to have profound effects on adult disease susceptibility. Genistein, a naturally occurring isoflavone found in soy, is recognized as a dietary estrogen as it interacts with both estrogen receptor (ER)-alpha and ER-beta. Human exposure to genistein is predominantly through dietary consumption of soy products, however, its use as nutritional supplements and pharmaceutical agents has dramatically increased due to the presumed beneficial effects of phytoestrogens in preventing cardiovascular diseases and cancer. Ironically, the potential deleterious effects of dietary estrogens, especially if exposure occurs during critical stages of development, remain poorly understood. Of concern are the well-documented carcinogenic effects of prenatal exposure to diethylstilbestrol (DES) and the wide exposure of infants and children to soy-based formulas. We have developed a mouse model to investigate the potential adverse effects of exposing the developing routine neonate to genistein. Outbred female CD-1 mice were treated on days 1-5 with equivalent estrogenic doses of genistein (50 mg/kg/day) or DES (0.001 mg/kg/day) dissolved in corn oil, or corn oil alone (control), and sacrificed at varying ages. A 35% and 31% incidence of uterine adenocarcinoma were found in aged mice neonatally treated with genistein (50 mg/kgf day) and DES (0.001mg/kg/day), respectively. A higher dose of DES (lmg/kg/day) caused a 95% incidence of the cancer. In this proposal, we will test the hypothesis that neonatal exposure to estrogenic compounds induces 1) aberrant methylation of 5'CpG islands of specific genes, and 2) that these changes persist in adult uterine tissues leading to """"""""permanent"""""""" changes in gene expression profiles in the adult uterus, resulting in a higher propensity for uterine tumorigenesis in this mouse model.
In Aim 1, we will use a highly innovative technology (methylation-sensitive DNA fingerprinting or MS-AP-PCR) to identify genes that are hyper- or hypomethylated in neonatal and adult uteri from mice neonatally exposed to DES or genistein as compared to control (unexposed) animals.
In Aim 2, we will perform global gene profiling analyses to identify gene sets that are up - or down - regulated in adult uteri from animals exposed neonatally to estrogens when compared to those without exposure. By comparing the results obtained from Aim 1 and Aim 2 we expect to establish a link between hyper- (silencing) or hypo- (release from silencing) of specific genes induced by neonatal estrogen exposure that are of relevancy to cancer susceptibility and development in the adult uteri, Results from these studies are expected to enhance our understanding of the mechanistic basis of adult diseases caused by developmental exposure to dietary estrogens. Future studies along this line of investigation will address impacts of other environmental estrogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES013071-04
Application #
7101744
Study Section
Special Emphasis Panel (ZRG1-ENR (50))
Program Officer
Heindel, Jerrold
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2006-09-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$149,893
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ho, Shuk-Mei; Cheong, Ana; Adgent, Margaret A et al. (2017) Environmental factors, epigenetics, and developmental origin of reproductive disorders. Reprod Toxicol 68:85-104
Perera, Frederica; Tang, Wan-yee; Herbstman, Julie et al. (2009) Relation of DNA methylation of 5'-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS One 4:e4488
Tang, Wan-Yee; Newbold, Retha; Mardilovich, Katerina et al. (2008) Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology 149:5922-31
Bakshi, Shlomo; Zhang, Xiang; Godoy-Tundidor, Sonia et al. (2008) Transcriptome analyses in normal prostate epithelial cells exposed to low-dose cadmium: oncogenic and immunomodulations involving the action of tumor necrosis factor. Environ Health Perspect 116:769-76
Perera, Frederica P; Herbstman, Julie B (2008) Emerging technology in molecular epidemiology: what epidemiologists need to know. Epidemiology 19:350-2
Tam, Neville N C; Szeto, Carol Ying-Ying; Sartor, Maureen A et al. (2008) Gene expression profiling identifies lobe-specific and common disruptions of multiple gene networks in testosterone-supported, 17beta-estradiol- or diethylstilbestrol-induced prostate dysplasia in Noble rats. Neoplasia 10:20-40
Miller, Rachel L; Ho, Shuk-Mei (2008) Environmental epigenetics and asthma: current concepts and call for studies. Am J Respir Crit Care Med 177:567-73
Keri, Ruth A; Ho, Shuk-Mei; Hunt, Patricia A et al. (2007) An evaluation of evidence for the carcinogenic activity of bisphenol A. Reprod Toxicol 24:240-52
Ho, Shuk-mei; Tang, Wan-yee (2007) Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases. Reprod Toxicol 23:267-82
Tang, Wan-yee; Ho, Shuk-mei (2007) Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord 8:173-82

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