2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other agonists of the Ah receptor (AhR) are thought to elicit their effects by altering gene expression in susceptible cells. The goals of this research are to determine the biological activity, cell specificity and dose-response characteristics of growth regulatory members of the human Ah gene battery, and to identify proteins that may be used to monitor exposed people. The long term objective of this research is to elucidate the events that occur in humans exposed to AhR agonists, and to test the hypothesis that the species and tissue-specific effects of TCDD are caused by the altered expression of specific subsets of genes that are regulated by the AhR.
The specific aims of this proposal are: 1) To characterize two TCDD-responsive cDNA clones, designated clone 1 and clone 141, that represent previously unidentified human genes. The structure, complexity and function these clones and their protein products will be determined. 2) To determine the tissue specificity of certain members of the human Ah gene battery, including clone 1 and clone 141, and alpha-human chorionic gonadotropin, interleukin-1beta, ornithine decarboxylase, plasminogen activator inhibitor-2, and transforming growth factor-alpha. Constitutive expression in normal human tissues and inducibility in human epidermal keratinocytes will also be analyzed. 3) To determine if treatment with TCDD increases the rate of transcription of the genes identified in aim 2. 4) To determine if treatment with TCDD results in increased production of active IL-1beta and PAI-2. 5) To determine the dose-response, structure activity, and kinetics of induction of the growth regulatory members of the human Ah gene battery. This research will improve our knowledge of the toxic actions of Ah receptor agonists in a primary target tissue in man. The proposed measurements will improve our ability to extrapolate the human health risk of exposure to this class of compounds from known rodent bioassay results.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29ES006071-02
Application #
3465395
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1992-08-01
Project End
1997-06-30
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sutter, Carrie Hayes; Yin, Hong; Li, Yunbo et al. (2009) EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes. Proc Natl Acad Sci U S A 106:4266-71
Sutter, Carrie Hayes; Qian, Zheng; Hong, Yeon-Pyo et al. (2002) Genotyping human cytochrome: P450 1B1 variants. Methods Enzymol 357:53-8
Spink, D C; Spink, B C; Cao, J Q et al. (1998) Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells. Carcinogenesis 19:291-8
Crofts, F G; Sutter, T R; Strickland, P T (1998) Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by human cytochrome P4501A1, P4501A2 and P4501B1. Carcinogenesis 19:1969-73
Shimada, T; Gillam, E M; Sutter, T R et al. (1997) Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos 25:617-22
Spink, D C; Spink, B C; Cao, J Q et al. (1997) Induction of cytochrome P450 1B1 and catechol estrogen metabolism in ACHN human renal adenocarcinoma cells. J Steroid Biochem Mol Biol 62:223-32
Crespi, C L; Penman, B W; Steimel, D T et al. (1997) Development of a human lymphoblastoid cell line constitutively expressing human CYP1B1 cDNA: substrate specificity with model substrates and promutagens. Mutagenesis 12:83-9
Crofts, F G; Strickland, P T; Hayes, C L et al. (1997) Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human cytochrome P4501B1. Carcinogenesis 18:1793-8
Tritscher, A M; Seacat, A M; Yager, J D et al. (1996) Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats. Cancer Lett 98:219-25
Gastel, J A; Sutter, T R (1996) A control system for cDNA enrichment reactions. Biotechniques 20:870-5

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