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

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 off the abo ve study: (a) the low number of individuals tested, (b) in some of the comp arison tests, C57DL/6J mice (i.e. inbred B6 mice) were used as wild-type co ntrol mice. Since then we increased our laboratory breeding program and the reby 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 va riations expressed in toxicity within each group of c-src deficient mice. N evertheless, when a large enough number of individuals were tested two toxi c 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 whic h were commonly observed in TCDD-treated wild type mice, but not in c-src d eficient mice. The former trend was also confirmed by both liver lipid anal ysis and histological examinations of the affected livers. As for the bioch emical parameters, the hepatic nuclear protein binding to C/EBP (CCAAT/enha ncer binding protein) response element appears to be uniformly reduced by t he action of TCDD in +/+ mice, but not in -/+ or -/- mice. (C) 1999 Elsevie r Science Ireland Ltd. All rights reserved.