Arcaro K F, Yi L, Seegal R F, Vakharia D D, Yang Y, Spink D C, Brosch K, Gierthy J F
School of Public Health, State University of New York at Albany, 12222, USA.
J Cell Biochem. 1999 Jan 1;72(1):94-102.
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants whose effects on biological systems depend on the number of and the positions of the chlorine substitutions. In the present study we examined the estrogenicity of the fully ortho-substituted PCB, 2,2',6,6'-tetrachlorobiphenyl (2,2',6,6'-TeCB). This PCB was chosen as the prototypical ortho-substituted PCB to test the hypothesis that ortho-substitution of a PCB with no para- or meta-chlorine-substitutions results in enhanced estrogenic activity. The results indicate that 2,2',6,6'-TeCB is estrogenic both in vitro, in the MCF-7 cell focus assay, and in vivo, in the rat uterotropic assay. The estrogenic activity elicited by the addition of 5 microM 2,2',6,6'-TeCB to the medium of MCF-7 cultures was inhibited by the estrogen receptor (ER) antagonist, LY156758, suggesting that 2,2',6,6'-TeCB or a metabolite is acting through an ER-dependent mechanism. Results from competitive binding assays using recombinant human (rh) ER indicate that 2,2',6,6'-TeCB does not bind rhERalpha or rhERbeta. A metabolite of 2,2',6,6'-TeCB, 2,2',6,6'-tetrachloro-4-biphenylol (4-OH-2,6,2',6'-TCB), does bind rhERalpha and rhERbeta and is also 10-fold more estrogenic than 2,2',6,6'-TeCB in the MCF-7 focus assay; however, this metabolite is not detected in the medium of MCF-7 cultures exposed to 2,2',6,6'-TeCB. Taken together, the results suggest that the estrogenicity observed in human breast cancer cells and the rat uterus may be due to 1) an undetected metabolite of 2,2',6,6'-TeCB binding to the ER, 2) 2,2',6,6'-TeCB binding directly to a novel form of the ER, or 3) an unknown mechanism involving the ER.
多氯联苯（PCBs）是普遍存在的环境污染物，其对生物系统的影响取决于氯取代基的数量和位置。在本研究中，我们检测了完全邻位取代的多氯联苯2,2',6,6'-四氯联苯（2,2',6,6'-TeCB）的雌激素活性。选择这种多氯联苯作为典型的邻位取代多氯联苯，以检验以下假设：没有对氯或间氯取代的多氯联苯的邻位取代会导致雌激素活性增强。结果表明，2,2',6,6'-TeCB在体外的MCF-7细胞集落形成试验以及体内的大鼠子宫增重试验中均具有雌激素活性。向MCF-7培养物培养基中添加5 microM 2,2',6,6'-TeCB所引发的雌激素活性受到雌激素受体（ER）拮抗剂LY156758的抑制，这表明2,2',6,6'-TeCB或其代谢产物是通过ER依赖机制发挥作用的。使用重组人（rh）ER进行的竞争性结合试验结果表明，2,2',6,6'-TeCB不与rhERα或rhERβ结合。2,2',6,6'-TeCB的一种代谢产物2,2',6,6'-四氯-4-联苯酚（4-OH-2,6,2',6'-TCB）确实能与rhERα和rhERβ结合，并且在MCF-7集落形成试验中其雌激素活性也比2,2',6,6'-TeCB高10倍；然而，在暴露于2,2',6,6'-TeCB的MCF-7培养物培养基中未检测到这种代谢产物。综上所述，这些结果表明，在人乳腺癌细胞和大鼠子宫中观察到的雌激素活性可能是由于1）2,2',6,6'-TeCB的一种未检测到的代谢产物与ER结合，2）2,2',6,6'-TeCB直接与一种新型ER结合，或3）涉及ER的未知机制。
