TCDD and its structural analogs such as the polychlorinated dibenzofurans (PCDFs) appear to exert their effects through a mechanism requiring an initial interaction with the Ah receptor. Our goals are to determine dose response relationships for dioxin following chronic exposure in rodent models and accidental or occupational exposure in humans. We also attempt to characterize the molecular mechanisms that regulate cell specific actions of dioxin. Our studies have demonstrated that TCDD-mediated changes in cytochrome P-450 isozymes and growth factor pathways in a rat liver tumor promotion model are linear in the low dose region. In order to determine changes in gene expression at levels which approximate human exposures, we have developed a reverse transcriptase PCR method which can detect less than one mRNA per cell of some dioxin responsive genes. This method is also permitting us to examine TCDD's biochemical effects in blood samples from humans who had been occupationally or accidentally exposed to dioxin. These and other approaches have provided evidence that there is considerable interindividual variation in the magnitude of response to a given exposure. However, not all dioxin's effects are linearly related to target tissue dose. For example, we have shown that TCDD-mediated changes in hepatocyte cell proliferation and growth of preneoplastic lesions require relatively high doses to cause detectable changes. Our animal and human data are being used to construct biologically-based models for dioxin's effects. These models have been an important element in the estimation of human risks from dioxin exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES046004-09
Application #
3777514
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Xie, An; Walker, Nigel J; Wang, Desuo (2006) Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) enhances triggered afterdepolarizations in rat ventricular myocytes. Cardiovasc Toxicol 6:99-110
Haws, Laurie C; Su, Steave H; Harris, Mark et al. (2006) Development of a refined database of mammalian relative potency estimates for dioxin-like compounds. Toxicol Sci 89:4-30
Nyska, Abraham; Yoshizawa, Katsuhiko; Jokinen, Micheal P et al. (2005) Olfactory epithelial metaplasia and hyperplasia in female Harlan Sprague-Dawley rats following chronic treatment with polychlorinated biphenyls. Toxicol Pathol 33:371-7
Walker, Nigel J; Crockett, Patrick W; Nyska, Abraham et al. (2005) Dose-additive carcinogenicity of a defined mixture of ""dioxin-like compounds"". Environ Health Perspect 113:43-8
Brix, Amy E; Nyska, Abraham; Haseman, Joseph K et al. (2005) Incidences of selected lesions in control female Harlan Sprague-Dawley rats from two-year studies performed by the National Toxicology Program. Toxicol Pathol 33:477-83
Yoshizawa, Katsuhiko; Marsh, Tiwanda; Foley, Julie F et al. (2005) Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley Rats. Toxicol Sci 85:594-606
Hailey, James R; Walker, Nigel J; Sells, Donald M et al. (2005) Classification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds. Toxicol Pathol 33:165-74
Yoshizawa, Katsuhiko; Walker, Nigel J; Jokinen, Micheal P et al. (2005) Gingival carcinogenicity in female Harlan Sprague-Dawley rats following two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Toxicol Sci 83:64-77
Vezina, Chad M; Walker, Nigel J; Olson, James R (2004) Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression. Environ Health Perspect 112:1636-44
Wyde, Michael E; Braen, Angelique P J M; Hejtmancik, Milton et al. (2004) Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice. Toxicol Sci 82:34-45

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