Differential toxicities of TCDD in vivo among normal, c-src knockout, geldanamycin- and quercetin-treated mice

Abstract

Although we have previously reported the result of our preliminary study on the reduced toxic effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in vivo in male c-src deficient, −/+B6, 129-src tmlSor mice as compared to those in wild-type mice, there are still two major shortcomings of the above study: (a) the low number of individuals tested, (b) in some of the comparison tests, C57BL/6J mice (i.e. inbred B6 mice) were used as wild-type control mice. Since then we increased our laboratory breeding program and thereby the availability of B6, 129 −/+, −/− and true littermate wild-type +/+individual mice. The results of critical in vivo toxicity comparison tests, involving 6–13 mice per test group, showed that there are considerable variations expressed in toxicity within each group of c-src deficient mice. Nevertheless, when a large enough number of individuals were tested two toxic effects were found to be less expressed in src-deficient mice. They were: (a) excess fatty deposits and (b) the mottled appearance of the liver which were commonly observed in TCDD-treated wild type mice, but not in c-src deficient mice. The former trend was also confirmed by both liver lipid analysis and histological examinations of the affected livers. As for the biochemical parameters, the hepatic nuclear protein binding to C/EBP (CCAAT/enhancer binding protein) response element appears to be uniformly reduced by the action of TCDD in +/+ mice, but not in −/+or −/− mice.