Tumorpromovierende Dioxine, Furane und Biphenyle: In vitro-Untersuchungen der Wirkungsmechanismen von Zelltransformation, Wachstumsregulation und Zelldifferenzierung Abschlussbericht

The assessment of the tumor promoting potential of polychlorinated dioxins (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), furans and biphenyls is hampered by the following problems: - the toxic equivalency factor (TEF) approach can only be used for TCDD-like congeners; - strict additivity of the congeners is a prerequisite for the use of the TEF approach; -species- and cell-specific effects complicate the extrapolation of the experimental data to humans. The molecular mechanisms of tumor promotion by TCDD, dioxin-like and non dioxin-like PCBs were studied in cell cultures (promotion of the malignant transformation of mouse fibroblasts; growth stimulation of hepatocytes in primary cultures): - changes of arachidonic acid metabolism (enhancement of prostaglandin production and of the expression of the cyclooxygenases Cox-1 and Cox-2) occurred during long term-treatment of carcinogen-initiated fibroblasts with TCDD (after 3-4 weeks); - prostaglandin F 2#alpha# exhibited a tumor promoting activity on the transformation of fibroblasts and could in cooperation with other arachidonic metabolites cause the TCDD-mediated promotion; -inhibition of Cox-2 activity abolished the promoting effect of TCDD in hepatocytes (the target cells of TCDD in vivo) but not in fibroblasts (promotion of transformation); - growth stimulation by TCDD (maximally at 1 pM) was found in primary human and rat hepatocytes. The elucidation of changes in the arachidonic acid metabolism of TCDD-/PPCB-treated cell cultures may contribute to a deeper insight into the cell- and species-specific mechanisms of tumor promotion. (orig.)SIGLEAvailable from TIB Hannover: F98B191 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman