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-dioxin (TCDD) and its congeners has received considerable attention, the impact of advanced age on the biochemical effects and the pharmacokinetics of dioxins remains largely undetermined. In the present investigation, 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 [3H]TCDD doses ranging from 0.015 to 15 microgram/kg body wt. Determinations of hepatic marker enzyme activities for CYP1A1 (ethoxyresorufin O-deethylation, EROD) and 1A2 (acetanilide-4-hydroxylation, ACOH) indicated that the dose response curves for EROD induction by TCDD were nearly identical for the 2 age groups, but the ACOH induction response was greater in old mice. After receiving the 15 micrograms/kg dose, an increase (approximately 35%) in relative liver weight was observed 7 days after dosing in the 10-week mice, but not in the aged mice, and the hepatic concentration of TCDD was approximately 25% greater in young than old mice. No age difference was found in hepatic nuclear concentrations of TCDD. A dose-dependent increase in liver:fat tissue concentration ratios was noted at both ages, and adipose tissue and blood concentrations of TCDD did not vary significantly with age. In old mice however, TCDD concentrations in skin, kidney and muscle were all approximately twice those of young mice at the 15 micrograms/kg 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.
Pegram
R A
RA
Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Diliberto
J J
JJ
Moore
T C
TC
Gao
P
P
Birnbaum
L S
LS
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001835:Body Weight; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D008099:Liver / Q000033:anatomy & histology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010088:Oxidoreductases / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics* / Q000494:pharmacology
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C023738:acetanilide hydroxylase