2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) DISTRIBUTION AND CYTOCHROME P4501A INDUCTION IN YOUNG-ADULT AND SENESCENT MALE-MICE

While the developmental toxicology of 2,3,7,8-tetrachlorodibenzo-p-dio xin (TCDD) and its congeners has received considerable attention, the impact of advanced age on the biochemical effects and the pharmacokine tics of dioxins remains largely undetermined. In the present investiga tion, TCDD tissue distribution and cytochrome P4501A (CYP1A) induction were characterized in male C57BL/6N mice aged 10 weeks and 28 months at 7 days after administration of single oral [H-3]TCDD doses ranging from 0.015 to 15 mu g/kg body wt. Determinations of hepatic marker enz yme activities for CYP1Al (ethoxyresorufin O-deethylation, EROD) and 1 A2 (acetanilide-4-hydroxylation, ACOH) indicated that the dose respons e curves for EROD induction by TCDD were nearly identical for the 2 ag e groups, but the ACOH induction response was greater in old mice. Aft er receiving the 15 mu g/kg dose, an increase (35%) in relative liver weight was observed 7 days after dosing in the 10-week mice, but not i n the aged mice, and the hepatic concentration of TCDD was similar to 25% greater in young than old mice. No age difference was found in hep atic nuclear concentrations of TCDD. A dose-dependent increase in live r:fat tissue concentration ratios was noted at both ages, and adipose tissue and blood concentrations of TCDD did not vary significantly wit h age. In old mice however, TCDD concentrations in skin, kidney and mu scle were all approximately twice those of young mice at the 15 mu g/k g dose. These results suggest that advanced age may have differential effects on Ah receptor-mediated enzyme induction, while increased TCDD concentrations in certain tissues may have toxicological implications for older animals.