The long-range goal of this research is to develop an understanding of the mechanisms underlying the adverse health effects and toxicity resulting from exposure to complex mixtures of polycyclic aromatic hydrocarbons (PAH) and chromium, a carcinogenic metal often found as an environmental co-contaminant with PAHs. The objectives of this research project are, (1) to elucidate the mechanisms by which chromium affects inducible gene expression, and (2), to evaluate the effect of mixtures of benzo[a]pyrene (B[a]P), a prototypical PAH, and chromium on the post-translational modifications of chromatin remodeling proteins associated with epigenetic modulation of gene expression. Chromium exposure has been shown to alter inducible gene expression, to form chromium-DNA adducts and chromium-DNA cross-links, and to disrupt transcriptional activator/coactivator complexes. During the previous 4 years of this grant we have shown that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoters of inducible genes. We studied the effects of chromium on the expression of genes induced by B[a]P and showed that chromium disrupted the transcriptional regulation of phase I and phase II detoxification genes induced by B[a]P-dependent Ah receptor activation and the inducible expression of over 50 different genes involved in a variety of signal transduction pathways. These effects of chromium were the result of the inhibition of critical chromatin remodeling steps necessary for gene transactivation. Given the central role of histones in maintaining chromatin structure, for the next 5 years of this grant application we propose to test the hypothesis that exposure to mixtures of chromium and B[a]P causes specific histone modifications that generate transcriptionally inactive chromatin and induce non-additive gene expression effects that cannot be predicted from the individual effect of each mixture component. Results from this work will help to generate an understanding of the risks arising from exposure to chemical mixtures and to develop effective means to predict their health effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010807-10
Application #
7754396
Study Section
Special Emphasis Panel (ZRG1-DIG-F (02))
Program Officer
Balshaw, David M
Project Start
2001-01-16
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
10
Fiscal Year
2010
Total Cost
$339,965
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
Ko, Chia-I; Puga, Alvaro (2017) Does the Aryl Hydrocarbon Receptor Regulate Pluripotency? Curr Opin Toxicol 2:1-7
Wang, Qin; Kurita, Hisaka; Carreira, Vinicius et al. (2016) Ah Receptor Activation by Dioxin Disrupts Activin, BMP, and WNT Signals During the Early Differentiation of Mouse Embryonic Stem Cells and Inhibits Cardiomyocyte Functions. Toxicol Sci 149:346-57
Carreira, Vinicius S; Fan, Yunxia; Wang, Qing et al. (2015) Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes. Toxicol Sci 147:425-35
Carreira, Vinicius S; Fan, Yunxia; Kurita, Hisaka et al. (2015) Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult. PLoS One 10:e0142440
Sánchez-Martín, Francisco Javier; Fan, Yunxia; Carreira, Vinicius et al. (2015) Long-term Coexposure to Hexavalent Chromium and B[a]P Causes Tissue-Specific Differential Biological Effects in Liver and Gastrointestinal Tract of Mice. Toxicol Sci 146:52-64
Kurita, Hisaka; Schnekenburger, Michael; Ovesen, Jerald L et al. (2014) The Ah receptor recruits IKK? to its target binding motifs to phosphorylate serine-10 in histone H3 required for transcriptional activation. Toxicol Sci 139:121-32
Ovesen, Jerald L; Fan, Yunxia; Chen, Jing et al. (2014) Long-term exposure to low-concentrations of Cr(VI) induce DNA damage and disrupt the transcriptional response to benzo[a]pyrene. Toxicology 316:14-24
Ovesen, Jerald L; Fan, Yunxia; Zhang, Xiang et al. (2014) Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) analysis uncovers broad changes in chromatin structure resulting from hexavalent chromium exposure. PLoS One 9:e97849
Ko, Chia-I; Wang, Qin; Fan, Yunxia et al. (2014) Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells. Stem Cell Res 12:296-308
Wang, Qin; Chen, Jing; Ko, Chia-I et al. (2013) Disruption of aryl hydrocarbon receptor homeostatic levels during embryonic stem cell differentiation alters expression of homeobox transcription factors that control cardiomyogenesis. Environ Health Perspect 121:1334-43

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