Research Center for Environmental Bioscience and Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan.
Chem Res Toxicol. 2012 Mar 19;25(3):656-63. doi: 10.1021/tx200374s. Epub 2012 Feb 10.
Polybrominated diphenyl ethers (PBDEs) have been used in a variety of consumer products such as flame retardants and recently have been known to be widespread environmental pollutants, which probably affect biological functions of mammalian cells. However, the risk posed by PBDE metabolites has not been clarified. Our previous study suggested that bisphenol A (BPA), an endocrine-disrupting chemical, binds to protein disulfide isomerase (PDI) and inhibits its activity. PDI is an isomerase enzyme in the endoplasmic reticulum and facilitates the formation or cleavage of disulfide bonds. PDI consists of a, b, b', and a' domains and the c region, with the a and a' domains having isomerase active sites. In the present study, we tested the effects of 10 kinds of PBDE compounds and their metabolites on PDI. OH-PBDEs specifically inhibited the isomerase activity of PDI, with 4'-OH-PBDE more effective than 2' (or 2)-OH-PBDEs. 4'-OH-PBDE inhibited the isomerase activity of the b'a'c fragment but not that of ab and a'c, suggesting that the b' domain of PDI is essential for the inhibition by 4'-OH-PBDE. We also investigated the effects of these chemicals on the production of growth hormone (GH) in GH3 cells. In GH3 cells, levels of mRNA and protein of GH stimulated by T(3) were reduced by 4'-OH-PBDE and 4'-MeO-PBDE. The reduction in GH expression caused by these compounds was not changed by the overexpression or knockdown of PDI in GH3 cells, while these manipulations of PDI levels significantly suppressed the expression of GH. These results suggest that the biological effects of PBDEs differed depending on their brominated and hydroxylated positions.
多溴联苯醚（PBDEs）已被广泛应用于各种消费品，如阻燃剂，最近被认为是广泛存在的环境污染物，可能会影响哺乳动物细胞的生物学功能。然而，PBDE 代谢物所带来的风险尚未得到阐明。我们之前的研究表明，环境内分泌干扰物双酚 A（BPA）与蛋白二硫键异构酶（PDI）结合并抑制其活性。PDI 是内质网中的一种异构酶，可促进二硫键的形成或断裂。PDI 由 a、b、b'和 a'结构域以及 c 区组成，其中 a 和 a'结构域具有异构酶活性位点。在本研究中，我们测试了 10 种 PBDE 化合物及其代谢物对 PDI 的影响。OH-PBDE 特异性抑制 PDI 的异构酶活性，其中 4'-OH-PBDE 比 2'（或 2）-OH-PBDEs 更有效。4'-OH-PBDE 抑制 b'a'c 片段的异构酶活性，但不抑制 ab 和 a'c，表明 PDI 的 b'结构域对于 4'-OH-PBDE 的抑制是必需的。我们还研究了这些化学物质对 GH3 细胞中生长激素（GH）产生的影响。在 GH3 细胞中，T(3)刺激的 GH mRNA 和蛋白水平被 4'-OH-PBDE 和 4'-MeO-PBDE 降低。这些化合物引起的 GH 表达减少不受 GH3 细胞中 PDI 的过表达或敲低改变，而 PDI 水平的这些操作显著抑制了 GH 的表达。这些结果表明，PBDE 对 GH 表达的影响可能与它们的溴化和羟基化位置有关。
