Enan E, El-Sabeawy F, Moran F, Overstreet J, Lasley B
Department of Environmental Toxicology, and Institute of Toxicology and Environmental Health, University of California, Davis, USA.
Biochem Pharmacol. 1998 Apr 1;55(7):1077-90. doi: 10.1016/s0006-2952(97)00683-7.
At doses of 10-115 microg/kg, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decreased body and adipose tissue weights of mature female rats. Doses below 10 microg TCDD/kg decreased body and adipose tissue weights of immature, but not mature females. Doses of 2 and 10 microg 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 (E2, 15 microg/kg) increased TK and PKA activities and decreased MAP2K activity. In immature females, E2 decreased TK and PKA activities but not MAP2K activity. TCDD abolished the stimulatory effect of E2 on TK and PKA in mature females, and in immature females TCDD potentiated the negative effect of E2 on all three kinases. TCDD decreased binding of [3H]E2 to cytosolic and nuclear estrogen receptors (ERs) of mature and immature females, and antagonized the stimulatory effect of E2 on ER binding activity. E2 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 E2 action on TK activity in mature females, as well as E2 action on PKA activity in immature females. We hypothesize that TCDD antagonizes E2 action in female adipose tissues through disruption of common cytosolic signal transduction pathways.
在剂量为10 - 115微克/千克时，2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）降低了成熟雌性大鼠的体重和脂肪组织重量。低于10微克TCDD/千克的剂量降低了未成熟雌性大鼠的体重和脂肪组织重量，但对成熟雌性大鼠无此作用。2微克和10微克TCDD/千克的剂量分别在5天和7天后降低了未成熟和成熟雌性大鼠脂肪组织的表皮生长因子受体（EGFR）结合活性。在这些时间点，酪氨酸激酶（TK）、丝裂原活化蛋白激酶（MAP2K）和蛋白激酶A（PKA）的活性均降低。在成熟雌性大鼠中，雌二醇（E2，15微克/千克）增加了TK和PKA的活性，并降低了MAP2K的活性。在未成熟雌性大鼠中，E2降低了TK和PKA的活性，但未降低MAP2K的活性。TCDD消除了E2对成熟雌性大鼠TK和PKA的刺激作用，而在未成熟雌性大鼠中，TCDD增强了E2对所有三种激酶的负面影响。TCDD降低了[3H]E2与成熟和未成熟雌性大鼠胞质和核雌激素受体（ERs）的结合，并拮抗了E2对ER结合活性的刺激作用。E2增加了雌激素反应元件（ERE）和激活蛋白-1的DNA结合活性，而TCDD拮抗了这种作用。格尔德霉素是一种Src酪氨酸激酶抑制剂，可减轻TCDD对体重和脂肪组织重量的影响。格尔德霉素拮抗了TCDD对EGFR结合活性和TK活性的影响。在无细胞制剂中，TCDD拮抗了E2对成熟雌性大鼠TK活性的作用，以及E2对未成熟雌性大鼠PKA活性的作用。我们假设TCDD通过破坏常见的胞质信号转导途径拮抗E2在雌性脂肪组织中的作用。
