Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the epidermal growth factor receptor in hepatic plasma membranes of rainbow trout.
Time- and dose-dependent alterations in epidermal growth factor receptor (EGF-R) ligand binding and protein kinase activity were observed in hepatic plasma membranes of TCDD-treated rainbow trout. Trout were dosed by a single ip injection of TCDD in a corn oil vehicle. A single ip injection of TCDD (10 micrograms TCDD/kg body weight) caused a maximal reduction of EGF binding to hepatic plasma membranes by 10 days posttreatment which remained reduced until Day 40. EROD activity in the liver microsomes of TCDD-treated trout increased relative to untreated fish over the course of the study. Protein kinase C and tyrosine kinase activity as well as EGF receptor phosphorylation was greater in livers of treated than in those of control fish within 5 days but returned to control levels by 40 days postinjection. In a dose-response study, EGF binding was reduced in a dose-dependent manner with an ED50 of 0.17 micrograms TCDD/kg wet weight while EROD activity was induced with an ED50 of 0.79 micrograms TCDD/kg. The reduction in EGF binding was correlated to an increase in EROD activity, protein kinase C activity, and tyrosine kinase activity but was negatively correlated to EGF receptor phosphorylation. Of the parameters examined in both the time course and dose studies, protein kinase C was the best predictor of the reduction of EGF binding to hepatic plasma membranes of rainbow trout. The results from this study are consistent with the hypothesis that the mode of action of TCDD on the EGF receptor is in part mediated through the protein kinase C activity. It also suggests that the toxic mode of action of TCDD is similar in rainbow trout and mammals.
Newsted
J L
JL
Department of Fisheries and Wildlife, Michigan State University, East Lansing 48824-1222.
Giesy
J P
JP
D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D003634:DDT / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000032:analysis / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D010088:Oxidoreductases / Q000032:analysis; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011493:Protein Kinase C / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D014337:Trout
D000072317:Polychlorinated Dibenzodioxins; D004815:Epidermal Growth Factor; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C