Pleiotropic effect of the gene hairless on hepatotoxicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in mice.
Treatment of mice of the A2G-hr/+ congenic line with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in the development of hepatic porphyria over a period of 4 weeks. Female mice responded to a lesser extent than did males. The degree of porphyria in haired heterozygotes (hr/+) was less than in the corresponding hairless homozygotes (hr/hr) and the haired mice had lower resting metabolic rates than hairless mice. Adaptation of mice of either genotype to a 32-33 degrees C environment resulted in a decrease in resting metabolic rate and a reduction in hepatic porphyrin levels. Histologically-demonstrated necrotic changes in livers were accompanied by increased activity of alanine aminotransferase and sorbitol dehydrogenase in the plasma; however, there was no clear temporal trend in plasma enzyme levels. Elevated environmental temperature reduced the plasma alanine aminotransferase activity. The study provided evidence for a pleiotropic effect of variation at the hr locus being expressed in TCDD hepatotoxicity. Suggestions for mechanisms whereby the effect can be mediated through alterations in resting metabolic rate are made.
Greig
J B
JB
MRC Toxicology Unit, Carshalton, Surrey, UK.
Francis
J E
JE
Kay
S J
SJ
Lister
T
T
Ray
D E
DE
Seawright
A A
AA
Smith
A G
AG
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics*; D004147:Dioxins / Q000633:toxicity*; D051379:Mice; D008812:Mice, Hairless / Q000235:genetics; D008811:Mice, Inbred DBA; D009154:Mutation; D010101:Oxygen Consumption / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011164:Porphyrias / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D013385:Succinate Dehydrogenase; D000410:Alanine Transaminase; D014575:Uroporphyrinogen Decarboxylase