Halogenated hydrocarbon pollutants : biologic and toxic effects

Abstract

The effects of various halogenated hydrocarbon pollutants on hepatic microsomal drug and steroid metabolizing enzymes were determined in neonatal, immature and adult Long Evans rats. The teratogenic and/or fetotoxic effects of polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin were also examined using the C57BL/6N mouse. The organochlorine pesticides p,p'-DDE, heptachlor, chlordane, toxaphene and dieldrin, like phenobarbital (PB), induced hepatic microsomal formation of the 4,5-dihydrodiol, 9- and 3-hydroxy metabolites of benzo[a]pyrene and induced hepatic microsomal testosterone 16α- and 16β-hydroxylase in immature male Long Evans rats. These pesticides also induced microsomal metabolism of benzo[a]pyrene and testosterone at positions other than those of PB, indicating induction of cytochrome P-450 isozymes that are not induced by PB. The polychlorinated and polybrominated biphenyl isomers and congeners that were halogenated in two or more ortho positions resembled PB as inducers of hepatic microsomal metabolism of benzo (a) pyrene, typified by enhanced formation of the trans-4,5-dihydrodiol metabolite. In contrast 3,3',4,4'-tetrachlorobiphenyl-induced microsomes exhibited increased formation of the trans-7,8- and 9,10-dihydrodiol benzo[a]pyrene metabolites, as did 3-methylcholanthrene. The mono-ortho-substituted polychlorinated and polybrominated biphenyls are mixed-type inducers and resembled FireMaster BP-6 and Aroclor 1254 as inducers of hepatic microsomal benzo[a]pyrene metabolism. Neonatal exposure to Aroclor 1254 induced hepatic microsomal metabolism of benzo[a]pyrene in 11- and 21-day-old Long Evans rats of both sexes. Any transient induction of microsomal enzyme activities was dissipated by 60 days. In 60-, 90-, and 120-day-old male and female rats that had been treated with Aroclor 1254 as neonates, there were significant changes in the hepatic microsomal aryl hydrocarbon hydroxylase, ethoxyresorufin-0-deethylase and pentoxyresorufin-0-depentylase activities and in the hepatic microsomal metabolism of benzo[a]pyrene and testosterone. Neonatal imprinting of hepatic microsomal xenobiotic and steroid metabolizing enzymes by Aroclor 1254 did not resemble that of PB. Furthermore, females appeared to be more sensitive than males to PB imprinting, while males appeared to be more sensitive to Aroclor 1254 imprinting. Treatment of pregnant C57BL/6N mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in a 60% incidence of cleft palate and 90% incidence of hydronephrosis in the fetuses. Pretreatment with Aroclor 1254 markedly decreased the incidence of cleft palate (from 60 to 8%), while not affecting the occurrence of hydronephrosis.