He Bin, Rhodes-Brower Stacey, Miller Michael R, Munson Albert E, Germolec Dori R, Walker Vickie R, Korach Kenneth S, Meade B Jean
National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
Toxicol Appl Pharmacol. 2003 Nov 1;192(3):254-61. doi: 10.1016/s0041-008x(03)00282-5.
Octamethylcyclotetrasiloxane (D4) is a low molecular weight cyclic silicone used in the synthesis of larger silicone polymers and in the formulation of a variety of personal care products. The effects of oral D4 exposure in mice on serum estradiol levels, uterine wet weight, and uterine peroxidase activity were investigated. Additionally, in vitro estrogen receptor binding activity was evaluated. Serum estradiol levels decreased in a dose-dependent manner after exposure to 100 mg/kg to 1000 mg/kg D4. Studies with adrenalectomized animals demonstrated that the decreased serum estradiol levels were not due to elevated serum corticosterone levels. Uterine wet weights in ovariectomized mice were significantly increased in a dose-dependent manner by exposure to 250-1000 mg of D4/kg, but not by exposure to other silicone compounds tested (hexamethylcyclotrisiloxane, decamethylcyclopentasiloxane, decamethyltetrasiloxane, and octaphenylcyclotetrasiloxane). Uterine peroxidase activity, a marker for estrogenic activity, was also significantly increased in D4-exposed mice, but not in mice exposed to the other siloxanes. Pretreating mice with the estrogen receptor antagonist ICI 182,780 completely blocked the D4-induced increase in uterine weight, and ovariectomized estrogen receptor-alpha knockout mice showed no increases in uterine weights when orally exposed to D4 or estradiol. In an in vitro estrogen receptor binding assay, D4 showed significant competition with (3)H-estradiol for binding to estrogen receptor-alpha, but not estrogen receptor-beta. The data presented here indicate that D4 has weak estrogenic activity, and that these effects are mediated through estrogen receptor-alpha.
八甲基环四硅氧烷（D4）是一种低分子量的环状硅氧烷，用于合成更大的有机硅聚合物以及多种个人护理产品的配方。研究了小鼠口服D4对血清雌二醇水平、子宫湿重和子宫过氧化物酶活性的影响。此外，还评估了体外雌激素受体结合活性。暴露于100mg/kg至1000mg/kg的D4后，血清雌二醇水平呈剂量依赖性下降。对肾上腺切除动物的研究表明，血清雌二醇水平的下降并非由于血清皮质酮水平升高所致。暴露于250 - 1000mg D4/kg可使去卵巢小鼠的子宫湿重呈剂量依赖性显著增加，但暴露于其他测试的有机硅化合物（六甲基环三硅氧烷、十甲基环五硅氧烷、十甲基四硅氧烷和八苯基环四硅氧烷）则无此现象。子宫过氧化物酶活性作为雌激素活性的标志物，在暴露于D4的小鼠中也显著增加，但暴露于其他硅氧烷的小鼠中未增加。用雌激素受体拮抗剂ICI 182,780预处理小鼠可完全阻断D4诱导的子宫重量增加，去卵巢的雌激素受体α基因敲除小鼠口服D4或雌二醇后子宫重量未增加。在体外雌激素受体结合试验中，D4与³H - 雌二醇竞争结合雌激素受体α有显著作用，但与雌激素受体β无此作用。此处呈现的数据表明D4具有弱雌激素活性，且这些作用是通过雌激素受体α介导的。
