(1) NSC Z

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1 (1) NSC Z

2 (1) NSC Z epi-PGF-2α 8-epi-PGF-2α hormone-like effect TCDD TPA TNF-α TCDD (dioxins) PGF-2α TCDD TCDD TNF-α TCDD dioxins TCDD 8-epi-PGF-2α TCDD Abstract For the last 40 years, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. Epidemiological evidence TNF-α suggests that the increased incidence of a TNF-α variety of human cancers, such as lymphoma, leukemia and liver and breast cancers, might TCDD TNF-α be attributed to exposure to these agents. Dioxins are a class of highly toxic and 8-Epi-PGF-2α TCDD broadly dispersed environmental (free contaminants that may pose significant risk to human health. Most dioxins are resistant to radical) environmental and biological degradation 8-epi-PGF-2α and once formed, disperse throughout the (autacoid) atmosphere, soil, and water. Although environmental concentrations of dioxins are 2

3 generally low, they bioaccumulate in human food stuffs because of their lipophilicity and stability. TCDD is a member of the class of dioxins and produces biological effects in experimental animals include cancer, teratogenicity and immunotoxicity and reproductive/developmental effects. TCDD also produces changes at the molecular and biochemical levels. Experimental animal model will be conducted in this project to evaluate the response biomarkers exposed to dioxins. These include (1) Analysis of TNF-α production TNF-α may sensitize and activate phagocytic cells to agents that induce them to release free radicals, it may act as an amplifing loop in TCDD-induced oxidative stress. (2) Quantitative analysis of 8-epi-PGF-2α One of the molecular mechanisms underlying TCDD toxicity might be common to all mammalia and is thought through the generation of free radicals. Specific analysis of 8-epi-PGF-2α may afford an opportunity to evaluate the status of excessive lipid peroxidation in vivo. We used two kind of animal model experiments in this study. First, in two-stage carcinogenesis experiment, we compared the promoting activity of TCDD to TPA, a well-known promoter. Then, collected the serum of mice to investigate the trend of TNF-α concentration to see whether TNF-α is a suitable toxic responsive marker or not. In addition, gastric intubation experiment was conducted in rats to analyze the urinary 8-epi-PGF-2α induced by TCDD. In this study, TCDD performed no promoting activity in the two-stage mice skin model when compared with TPA, and we also found that the serum concentration of TNF-α did not increase when the mice accumulatively exposed to TCDD. Therefore, TNF-α is not suitable to be an effective marker. 8-epi-PGF-2α concentration in the urine of rat performed highly sensitivity after TCDD exposure. So it`s may be a good effective marker. Keyword: Dioxins, toxic response marker, tumor necrosis factor, free radical TCDD P450 CYP1A1 aryl hydrocarbon receptor, AhR potent promoter diethylnitrosamine proliferation sensitivity specificity exposure and outcome PGF2 vasular reperfusion paracetamol F2-isoprostane 8-epi-PGF2 8-epi-PGF-2α biological 3

4 activity autacoid TNF-α TCDD TCDD TNF-α TCDD TCDD g dioxins oxidative stress response TPA lipid peroxidation TCDD TCDD TCDD TCDD dioxins CYP1A1 TCDD P450 TNF-α autoxidation TCDD by-product superoxide TNF-α anion hydroxyl radical TNF-α TCDD TNF-α - TCDD TNF-α TCDD TNF-α TNF-α 8-epi-PGF-2α 8-epi-PGF-2α TCDD µg TNF-α TCDD TCDD 1997 IARC TNF-α DNA 4

5 TCDD PGF2-α TCDD 8-epi-PGF-α mitogen 1. bis-allylic arachidonoyl radicals PGG PGF F-type PGF2-α 2. cyclooxygenase TCDD PGF2-α Environmental Health Perspective. PGF2-α TCDD TCDD 1. Beutler, B A: The role of tumor PGF2-α necrosis factor in health and disease. J. Rheumatol TCDD 26(57):16-21, 1999 PGF2-α 2. Delanty, N., Reilly, M., Fitzgerald, D J., J. Lawson, J A., PGF2-α and Fitzgerald, G A., 8-Epi PGF2 PGF2-α alpha: specific analysis of an TCDD isoeicosanoid as an index of oxidant stress in vivo, Br. J. Clin. Pharmacol., 42(1):15-9 (1996) PGF2-α TCDD 3. Fan F. Yan B. Wood G. Viluksela M. Rozman KK. Cytokines (IL-1beta and TNFalpha) in TNF-α TCDD relation to biochemical and immuno-logical effects of TNF-α 2,3,7,8-tetrachlorodibenzo-p-diox in (TCDD) in rats. Toxicology. TCDD 116(1-3):9-16, 1997 Jan. TNF-α TCDD 4. Fukunaga M. Makita N. Roberts LJ 2nd. Morrow JD. Takahashi K. Badr KF. Evidence for the PGF2-α existence of F2-isoprostane PGF2-α receptors on rat vascular smooth TCDD muscle cells. American Journal of 5

6 Physiology. 264(6 Pt 1):C , 1993 Jun. 6