MECHANISMS OF GENDER-SPECIFIC TCDD-INDUCED TOXICITY IS GUINEA-PIG ADIPOSE-TISSUE

After treatment with TCDD, the activities of cytosolic AhR-associated c-Src kinase, microsomal protein kinase C (nPKC epsilon), microsomal c -Src kinase, nuclear p(44/42) MAPK, c-Jun N terminus kinase, and the a mount of microsomal pan-Ras protein were different in males and female s. TCDD did not decrease body or adipose tissue weights in transgenic src-deficient male mice as compared to their wild-type littermates, an d the activity of AhR-associated c-Src kinase was not increased by TCD D in src-deficient male mice. Similar results were obtained when TCDD was given to male guinea pigs treated with the Src-kinase inhibitor, g eldanamycin, 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 femal e 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. (C) 1998 Elsevier Science Inc.