Mechanisms of gender-specific TCDD-induced toxicity in 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 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.
Enan
E
E
Department of Environmental Toxicology and Institute of Toxicology and Environmental Health, University of California, Davis 95616, USA. eeenan@ucdavis.edu
El-Sabeawy
F
F
Overstreet
J
J
Matsumura
F
F
Lasley
B
B
D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D016227:Benzoquinones; D001835:Body Weight / Q000187:drug effects; D000081247:CSK Tyrosine-Protein Kinase; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology; D012727:Sex Characteristics; D018631:ras Proteins / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D000072317:Polychlorinated Dibenzodioxins; D011809:Quinones; D004958:Estradiol; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D018631:ras Proteins; C001277:geldanamycin