The long-term objective of this proposal is to understand the molecular mechanisms underlying the biological responses to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) exposure. TCDD, the prototypic dioxin and a model for many other organochlorinated compounds, produces many apparently unrelated biological effects, ranging from chloracne in humans to developmental teratogenesis, tumor promotion, thymic atrophy, wasting syndrome and death in laboratory animals. In addition, TCDD, a rodent carcinogen, is strongly suspected of being carcinogenic also in humans. The molecular basis of the biological effects of TCDD is largely unknown. Dioxin is a ligand for the aromatic hydrocarbon (Ah) receptor (AHR), which, as a dimer with the Ah receptor nuclear translocator protein ARNT, mediates the transcriptional activation of genes in the CYP 1 family of cytochrome P450 monooxygenases. However, activation of the CYP1A1, CYP1A2 and CYP1 B1 genes, although one of the best characterized effects of Ah receptor activation by TCDD, does not adequately explain the diversity of TCDD effects. Our recent global expression profiling analyses of human hepatoma cells shows that exposure to dioxin induces or represses a total of more than 300 genes, with repression being the more frequent. Induction may readily be explained by the transactivating potential of the AHR, but gene repression is a novel effect of the activated AHR that is uncharacterized at the molecular level. The goal of the experiments proposed here is to define and characterize the regulatory interactions between the activated AHR and other transcription factors, co-regulators and chromatin remodeling factors responsible for the effects of dioxin on gene expression. The major objectives of this work are, (1) to define the role of discrete domains of the AHR in gene regulation; (2) to use proteomic analyses to identify AHR coregulatory partners in gene induction and repression; and (3) to clone the promoters of AHR regulated genes and characterize their response to dioxin exposure. Results from these experiments will be crucial for our understanding of the long-range biological consequences of exposure to dioxin and to other organochlorinated compounds and will help formulate an adequate rationale to deal with health problems arising from an ever-increasing exposure to these environmental agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006273-11
Application #
6951895
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (03))
Program Officer
Heindel, Jerrold
Project Start
1993-09-30
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
11
Fiscal Year
2005
Total Cost
$356,344
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
Kurita, Hisaka; Carreira, Vinicius S; Fan, Yunxia et al. (2016) Ah receptor expression in cardiomyocytes protects adult female mice from heart dysfunction induced by TCDD exposure. Toxicology 355-356:9-20
Ko, Chia-I; Fan, Yunxia; de Gannes, Matthew et al. (2016) Repression of the Aryl Hydrocarbon Receptor Is Required to Maintain Mitotic Progression and Prevent Loss of Pluripotency of Embryonic Stem Cells. Stem Cells 34:2825-2839
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Mongan, Maureen; Meng, Qinghang; Wang, Jingjing et al. (2015) Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis. J Biol Chem 290:19770-9
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
Winans, Bethany; Nagari, Anusha; Chae, Minho et al. (2015) Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses. J Immunol 194:4446-57
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

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