Differential toxicities of TCDD in vivo among normal, c-src knockout, geldanamycin- and quercetin-treated mice
D Y Dunlap1, M J Moreno-Aliaga, Z Wu
1Department of Environmental Toxicology and the Center for Environmental Health Science, University of California, Davis 95616, USA.
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.
Insights
Male c-src deficient mice show reduced toxicity from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), specifically less fatty liver deposits and altered liver appearance. This suggests c-src plays a role in TCDD toxicity pathways.
Area of Science:
- Toxicology
- Molecular Biology
- Genetics
Background:
- Previous studies indicated reduced 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity in c-src deficient mice.
- Limitations included small sample sizes and inconsistent wild-type controls.
Purpose of the Study:
- To re-evaluate TCDD toxicity in c-src deficient mice with improved methodology.
- To investigate the role of c-src in TCDD-induced toxic effects and biochemical alterations.
Main Methods:
- In vivo toxicity comparison tests using male c-src deficient (-/+) and wild-type (+/+) mice.
- Liver lipid analysis and histological examinations.
- Assessment of hepatic nuclear protein binding to C/EBP response elements.
Main Results:
- TCDD-treated wild-type mice exhibited excess fatty deposits and mottled livers, unlike c-src deficient mice.
- Histological and lipid analyses confirmed reduced hepatic steatosis in c-src deficient mice.
- TCDD uniformly reduced hepatic nuclear protein binding to C/EBP in wild-type mice, but not in c-src deficient mice.
Conclusions:
- c-src deficiency significantly mitigates specific TCDD-induced toxic effects, including hepatic steatosis.
- The c-src pathway is implicated in TCDD's biochemical actions on hepatic nuclear protein binding.
- Increased sample sizes confirm the protective role of c-src deficiency against TCDD toxicity.
