Some non-genotoxic agents cause epigenetic changes, including aberrant DNA methylation. A subset of these drug, called endocrine disrupters -synthetic chemicals resembling natural hormones-, have profound effects on development and fertility. The central hypothesis of the proposal is that developing germ cells, which undergo genome-wide epigenetic reprogramming, are especially vulnerable to the epigenetic effects of endocrine disrupters. Fetal germ cells provide an excellent study system to reveal the origin of transgenerational epigenetic effects. This proposal seeks to identify epigenetic changes in fetal germ cells after intrauterine exposure to selected endocrine disrupters. To address the central hypothesis, the specific aims are to: 1) Determine the methylation status of the H19/lgf2 imprinting control region (ICR) in perinatal germ cells after fetal exposure to endocrine disrupting chemicals;2) Assess global transcription changes caused by endocrine disrupters in fetal germ cells and gonadal somatic cells;and 3) Identify targets for aberrant hypermethylation by endocrine disrupters, in mouse female and male germ cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015185-05
Application #
7885525
Study Section
Special Emphasis Panel (ZES1-LWJ-E (EP))
Program Officer
Heindel, Jerrold
Project Start
2006-09-22
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$398,022
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Iqbal, Khursheed; Tran, Diana A; Li, Arthur X et al. (2016) High type I error and misrepresentations in search for transgenerational epigenetic inheritance: response to Guerrero-Bosagna. Genome Biol 17:154
Szabó, Piroska E (2016) Response to ""Variable directionality of gene expression changes across generations does not constitute negative evidence of epigenetic inheritance"" Sharma, A. Environmental Epigenetics, 2015, 1-5. Genome Biol 17:105
Szabó, Piroska E (2015) Response to: the nature of evidence for and against epigenetic inheritance. Genome Biol 16:138
Iqbal, Khursheed; Tran, Diana A; Li, Arthur X et al. (2015) Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogramming. Genome Biol 16:59
Lee, Dong-Hoon; Tran, Diana A; Singh, Purnima et al. (2011) MIRA-SNuPE, a quantitative, multiplex method for measuring allele-specific DNA methylation. Epigenetics 6:212-23
Kang, Eun-Rim; Iqbal, Khursheed; Tran, Diana A et al. (2011) Effects of endocrine disruptors on imprinted gene expression in the mouse embryo. Epigenetics 6:937-50
Abe, Masanobu; Tsai, Shirley Y; Jin, Seung-Gi et al. (2011) Sex-specific dynamics of global chromatin changes in fetal mouse germ cells. PLoS One 6:e23848
Iqbal, Khursheed; Jin, Seung-Gi; Pfeifer, Gerd P et al. (2011) Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A 108:3642-7