Biochemical Imprinting by Environmental Chemicals

Greene, Frank

Abstract

The broad objective of this proposal is to investigate the long-term effects of perinatal exposure to chemicals found in the environment on the development and regulation of enzymes of xenobiotic and steroid metabolism. Benzo(Alpha)pyrene, an important representative of the general class of polycyclic hydrocarbons to which we are commonly exposed, will be used as a model compound. B(Alph)P will be administered to pregnant inbred rats (CD F/Crl BR) and mice (C57BL/6J, DBA/2J, C3H/HeJ) and aryl hydrocarbon hydroxylase (AHH) activities will be determined in liver, lungs, kidney, small intestine and skin of the offspring when they are 8-10 weeks old. We will also evaluate the effects of perinatal B(Alpha)P exposure on the hepatic metabolism of aminopyrine and diazepam. In addition, the metabolic profiles of B(Alpha)P and testosterone (T) will be determined in liver microsomes showing changes in AHH activities. The metabolic profiles of B(Alpha)P and T will be correlated with the cytochrome P-450 isozyme composition as determined by polyacrylamide gel electrophoresis. Experiments will also be conducted to determine the dose-response relationships of perinatal exposure to B(Alpha)P and to compare the effects of pre- and post-natal exposure to B(Alpha)P on the AHH of the adult. The potential biological significance of perinatal exposure to B(Alpha)P will be assessed by comparing: 1) the ability of microsomes of B(Alpha)P exposed and control rats to activate[14C]B(Alpha)P to metabolites that bind covalently to DNA; 2) susceptibility to both 3-methycholanthrene and B(Alpha)P-induced fibrosarcomas in three strains of mice chosen for differences in their inducibility of AHH and their sensitivity to polycyclic hydrocarbon-induced tumor formation. We feel that the experiments outlined in this proposal will provide a better understanding of the mechanisms by which early exposure of the unborn child to foreign compounds influences the regulation of normal development and inducibility of the cytochrome P-450 system of adults and how such exposure influences the incidence of environmentally-induced cancer, and the ability of adults to metabolize drugs and environmental chemicals.