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

Abstract

At doses of 10–115 μg/kg, 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) decreased body and adipose tissue weights of mature female rats. Doses below 10 μg TCDD/kg decreased body and adipose tissue weights of immature, but not mature females. Doses of 2 and 10 μg TCDD/kg decreased adipose tissue epidermal growth factor receptor (EGFR) binding activity 5 and 7 days later in immature and mature females, respectively. At these times, there was a decrease in the activities of tyrosine kinase (TK), mitogen-activated protein kinase (MAP2K), and protein kinase A (PKA). In mature females, estradiol (E 2, 15 μg/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 abolished the stimulatory effect of E 2 on TK and PKA in mature females, and in immature females TCDD potentiated the negative effect of E 2 on all three kinases. TCDD decreased binding of [ 3H]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. Geldanamycin, 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 preparations, TCDD antagonized E 2 action on TK activity in mature females, as well as E 2 action on PKA activity in immature females. We hypothesize that TCDD antagonizes E 2 action in female adipose tissues through disruption of common cytosolic signal transduction pathways.