Mills, Jeremy J.; (1990) The effect of halogenated dioxins on the action of epidermal growth factor in mammalian systems. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

2.3.7.8-Tetrachlorodibenzo-p-dioxin (TCDD) partially blocks the incorporation of either 5-bromodeoxyuridine (BrdU) or [3H]-methyl thymidine into the DNA of primary rat hepatocytes stimulated to divide by epidermal growth factor (EGF). Flow cytometry was used to measure the incorporation of BrdU in DNA by differential staining with propidium iodide and fiuorescein-iabelled antibodies to BrdU residues. Pretreatment for 3 hr with TCDD (40 nM) caused a twofold reduction in the level of BrdU incorporated into F344 primary rat hepatocytes maximally stimulated with EGF (20 ng/ml). A similar effect was seen when the incorporation of labelled thymidine was measured. Using this latter technique a dose response curve for the action of TCDD was obtained; the ED50 dose of TCDD was 40 pM. Three structural analogues of TCDD, namely 2.3.7.8-tetrabromodibenzo-p-dioxin, 3,3',4,4'-tetrachloroazoxybenzene, and 1,2,3,4-tetrachlorodibenzo-p-dioxin, were examined in this system, and had ED50 values which were ranked in the same order as the known differences in their in vivo toxicity. There was no effect of either pertussis toxin or the glucocorticoid, dexamethasone, in this system. Insulin, vasopressin and a-thrombin proved unable to influence the inhibition of DNA synthesis induced by TCDD. However a phorbol ester (400 nM), antagonised the effect of TCDD. The effect of TCDD and exogenous EGF on the development of the neonatal kidney in BALB/C, C57BL710, DBA/2 and hybrid B10D2/f1 mice was examined. Animals were dosed with either TCDD (20 μg/kg, s.c.) or fifteen, daily doses of EGF (0.5 μg/g, s.c.) from day 1 post partum. Various growth and developmental changes, eye-opening, incisor eruption, and weight gain, were measured. Both TCDD and EGF induced precocious eye-opening and incisor eruption compared to control animals, while TCDD inhibited weight gain. Histological analysis of the kidneys showed a progressive TCDD-related agenesis and hydronephrosis. Mice treated with EGF did not show these lesions.

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