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Mechanisms of gender-specific TCDD-induced toxicity in guinea pig adipose tissue
E Enan1, F El-Sabeawy, J Overstreet
1Department of Environmental Toxicology and Institute of Toxicology and Environmental Health, University of California, Davis 95616, USA. eeenan@ucdavis.edu
Abstract:
After treatment with TCDD, the activities of cytosolic AhR-associated c-Src kinase, microsomal protein kinase C (nPKC epsilon), microsomal c-Src kinase, nuclear p44/42 MAPK, c-Jun N terminus kinase, and the amount of microsomal pan-Ras protein were different in males and females. TCDD did not decrease body or adipose tissue weights in transgenic src-deficient male mice as compared to their wild-type littermates, and the activity of AhR-associated c-Src kinase was not increased by TCDD in src-deficient male mice. Similar results were obtained when TCDD was given to male guinea pigs treated with the Src-kinase inhibitor, geldanamycin. Treatment with estradiol protected male guinea pigs from TCDD-induced wasting. TCDD induced similar changes in protein tyrosine kinase activity in adipose tissues of castrated male and intact female guinea pigs. The gender-specific mechanisms of TCDD-induced toxicity appear to involve c-Src kinase, nPKC epsilon, and pan-Ras, as well as overlap in the cytosolic signal transduction pathways of TCDD and sex steroids.
Insights
TCDD toxicity differs between sexes, involving specific kinases and proteins. Src-deficient mice and kinase inhibitors reveal c-Src kinase
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a potent environmental toxicant.
- Its toxicity mechanisms, particularly gender-specific effects, are not fully understood.
- Signal transduction pathways are implicated in TCDD's biological activity.
Purpose of the Study:
- To investigate the gender-specific mechanisms of TCDD-induced toxicity.
- To identify key signaling molecules involved in TCDD's effects on male and female subjects.
- To explore the role of c-Src kinase and sex steroid pathways in TCDD toxicity.
Main Methods:
- Comparative analysis of protein kinase activities and protein levels in male and female mice and guinea pigs after TCDD exposure.
- Utilized transgenic src-deficient mice to assess the role of c-Src kinase.
- Employed a Src-kinase inhibitor (geldanamycin) and estradiol treatment in guinea pig models.
Main Results:
- TCDD altered the activity of cytosolic AhR-associated c-Src kinase, nPKC epsilon, nuclear p44/42 MAPK, c-Jun N terminus kinase, and pan-Ras protein levels differently in males and females.
- TCDD did not affect body or adipose tissue weights in src-deficient male mice, and c-Src kinase activity remained unchanged.
- Estradiol protected male guinea pigs from TCDD-induced wasting, and similar protein tyrosine kinase activity changes were observed in castrated males and intact females.
Conclusions:
- Gender-specific mechanisms of TCDD toxicity involve c-Src kinase, nPKC epsilon, and pan-Ras.
- Cytosolic signal transduction pathways for TCDD and sex steroids show overlap.
- c-Src kinase plays a crucial role in mediating TCDD's toxic effects, particularly in relation to body weight and adipose tissue.