Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol.
Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol.
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2,4,6-三氯-和2,3,4,5-四氯-4-联苯酚的二元混合物的附加雌激素活性。
DOI：
10.1006/taap.1997.8281
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发表时间：
1997
影响因子：
3.8
通讯作者：
Gaido,KW
中科院分区：
文献类型：
--
作者：
Ramamoorthy,K;Vyhlidal,C;Wang,F;Chen,I;Safe,S;McDonnell,DP;Leonard,LS;Gaido,KW
研究了2‘，4’，6‘-三氯-4-联苯(HO-PCB3)、2’，3‘，4’，4‘，5’-四氯-4-联苯(HO-PCB4)及其等摩尔混合物(HO-PCB3/HO-PCB4)在21日龄B6C3F1小鼠子宫、MCF-7和MDA-MB-231人乳腺癌细胞、HepG2细胞中的雌激素样活性。17β-雌二醇(E_2)(0.02μg/kg/d×3)处理后，子宫湿重、过氧化物酶活性和孕激素受体结合量均增加。HO-PCB_3、HO-PCB_4或HO-PCB_3/HO-PCB_4(等摩尔)剂量分别为18、73、183或366Mol/kg(×3)时，雌激素活性呈剂量依赖性增加，任何剂量均未观察到最大诱导效应，且混合物的活性是相加的。以[~3H]E_2为放射性配基，用竞争结合法测定了E_2、HO-PCB3、HO-PCB4和HO-PCB3/HO-PCB4与小鼠子宫雌激素受体(ER)的结合。IC50值分别为1.1×10−8、3.4×10−6、9.9×10−7和4.2 5×10−6M。HO-PCB3和HO-PCB4在10−5~10−6M的浓度范围内均能最大限度地诱导MCF-7细胞增殖、大鼠肌酸激酶和人补体C3(C3-LUC)报告基因活性，且比E2低103~104倍。HO-PCB_3/HO-PCB_4混合物在高浓度(10−~5M)时表现出活性，并对这些反应具有相加性。HO-PCB3和HO-PCB4在共转染C3-Luc和ER表达载体的人HepG2细胞中也具有雌激素样活性，并且HO-PCB4混合物的雌激素样活性是相加的。在转化人ER和β-GAL报告基因上游的双雌激素反应元件的酵母中也得到了类似的结果。在HO-PCB3/HO-PCB4与C3-Luc(405 ng/孔)和不同数量的ER表达质粒(270、27、2.7或0.27 ng/孔)共转染的HepG2细胞中，研究了不同ER表达对HO-PCB3/HO-PCB4潜在协同作用的影响。结果表明，随着ER水平的降低，E_2、HO-PCB3、HO-PCB4和HO-PCB3/HO-PCB4的诱导反应幅度也随之降低。然而，HO-多氯联苯混合物的活性在高水平和低水平的ER下都是相加的。将C3-Luc和不同数量的ER表达载体共转染人乳腺癌细胞MDA-MB-231，也得到了类似的结果。这项研究的结果表明，在小鼠子宫中的几种雌激素反应测试中，MCF-7、HepG2和MDA-MBA-231人类癌细胞；以及基于酵母的报告基因测试，HO-PCB3和HO-PCB4都显示出雌激素活性。这些化合物的等摩尔混合物的雌激素活性在ER表达的高水平和低水平上是相加的。
The estrogenic activity of 2′,4′,6′-trichloro-4-biphenylol (HO-PCB3), 2′,3′,4′,5′-tetrachloro-4-biphenylol (HO-PCB4), and an equimolar mixture of both compounds (HO-PCB3/HO-PCB4) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 and MDA-MB-231 human breast cancer cells, HepG2 cells, and in a yeast-based reporter gene assay. Treatment of the animals with 17β-estradiol (E2) (0.02 μg/kg/day ×3) resulted in increased uterine wet weight, peroxidase activity and progesterone receptor binding. Treatment with 18, 73, 183 or 366 μmol/kg (×3) doses of HO-PCB3, HO-PCB4, or HO-PCB3/HO-PCB4 (equimolar) caused a dose-dependent increase in estrogenic activity; a maximal-induced response was not observed at any dose and the activity of the mixture was additive. Binding of E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 to the mouse uterine estrogen receptor (ER) was determined in a competitive binding assay using [3H]E2 as the radioligand. The IC50 values were 1.1 × 10−8, 3.4 × 10−6, 9.9 × 10−7, and 4.25 × 10−6m, respectively. HO-PCB3 and HO-PCB4 maximally induced MCF-7 cell proliferation, rat creatine kinase, and human complement C3 (C3-LUC) reporter gene activity at concentrations of 10−5to 10−6m, and these compounds were 103to 104less potent than E2. The HO-PCB3/HO-PCB4 mixture was active at the high concentration (10−5m) and was additive for these responses. HO-PCB3 and HO-PCB4 also exhibited estrogenic activity in human HepG2 cells cotransfected with C3-LUC and an ER expression plasmid, and the estrogenic activity of the HO-PCB mixture was additive. Similar results were obtained in yeast transformed with the human ER and a double estrogen responsive element upstream of the β-gal reporter gene. The effects of variable ER expression on the potential synergistic interactions of HO-PCB3/HO-PCB4 were investigated in HepG2 cells cotransfected with C3-LUC (405 ng/well) and variable amounts of ER expression plasmid (270, 27, 2.7, or 0.27 ng/well). The results show that as ER levels decreased, the magnitude of the induction response by E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 also decreased. However, the activities of the HO-PCB mixture were additive at high and low levels of ER. Similar results were obtained in MDA-MB-231 cells cotransfected with C3-LUC and variable amounts of ER expression plasmid. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus; MCF-7, HepG2, and MDA-MBA-231 human cancer cells; and a yeast based-reporter gene assay, both HO-PCB3 and HO-PCB4 exhibited estrogenic activity. The estrogenic activity of an equimolar mixture of these compounds was additive at high and low levels of ER expression.
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DOI：
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发表时间：
1974
期刊：
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影响因子：
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DOI：
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