INTERRUPTION OF ESTRADIOL SIGNAL-TRANSDUCTION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) THROUGH DISRUPTION OF THE PROTEIN-PHOSPHORYLATION PATHWAY IN ADIPOSE TISSUES FROM IMMATURE AND MATURE FEMALE RATS

At-doses of 10-115 mu g/kg, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decreased body and adipose tissue weights of mature female rats. Dose s below 10 mu g TCDD/kg decreased body and adipose tissue weights of i mmature, but not mature females. Doses of 2 and 10 mu g TCDD/kg decrea sed adipose tissue epidermal growth factor receptor (EGFR) binding act ivity 5 and 7 days later in immature and mature females, respectively. At these times, there was a decrease in the activities of tyrosine ki nase (TK), mitogen-activated protein kinase (MAP2K), and protein kinas e A (PKA). In mature females, estradiol (E-2,,15 mu g/kg) increased TK and PKA activities and decreased MAP2K activity. In immature females, E-2 decreased TK and PKA activities but not MAP2K activity. TCDD abol ished the stimulatory effect of E-2 on TK and PKA in mature females, a nd in immature females TCDD potentiated the negative effect of E-2 on all three kinases. TCDD decreased binding of [H-3]E-2 to cytosolic and nuclear estrogen receptors (ERs) of mature and immature females, and antagonized the stimulatory effect of E-2 on ER binding activity. E-2 increased DNA binding activity of the estrogen response element (ERE) and activator protein-1, and TCDD antagonized this effect. Geldanamyci n, an inhibitor of Src tyrosine kinase, reduced the effects of TCDD on body and adipose tissue weights. Geldanamycin antagonized the effects of TCDD on EGFR binding activity and TK activity. In cell-free prepar ations, TCDD antagonized E-2 action on TK activity in mature females, as well as E-2 action on PKA activity in immature females. We hypothes ize that TCDD antagonizes E-2 action in female adipose tissues through disruption of common cytosolic signal transduction pathways. (C) 1998 Elsevier Science Inc.