Effects of Polybrominated Diphenyl Ethers (PBDEs) and Their Derivatives on Protein Disulfide Isomerase Activity and Growth Hormone Release of GH3 Cells

Abstract

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.

Protein-disulfide Isomerase Regulates the Thyroid Hormone Receptor-mediated Gene Expression via Redox Factor-1 through Thiol Reduction-Oxidation

“…Previously we demonstrated that overexpression of PDI suppressed the GH mRNA expression in GH3 cells (28). We also clarified that the suppression of GH mRNA was mediated by the GH promoter in a luciferase reporter gene assay using the upstream region of GH (28).…”

“…These results suggested that isomerase activity rather than T 3 binding activity is involved in the regulation of the T 3 response. We previously found that knockdown of PDI did not increase GH expression (28). These results indicate that PDI does not suppress GH expression by trapping T 3 to inhibit TR-mediated gene expression.…”

Inhibition of the Functional Interplay between Endoplasmic Reticulum (ER) Oxidoreduclin-1α (Ero1α) and Protein-disulfide Isomerase (PDI) by the Endocrine Disruptor Bisphenol A

“…We previously found that BPA binds the PDI b′ domain and thereby inhibits the disulfide bond formation activity of PDI (25, 26). Because both Ero1α and BPA bind the PDI b′ domain, we hypothesized that BPA may interfere with Ero1α-mediated oxidation of PDI.…”

Fluorescence probe techniques to study the interaction between hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and protein disulfide isomerase (PDI)

“…However, some research teams have reported that bisphenol A (BPA), hydroxylated polychlorinated biphenyls (PCB), PBDEs and their derivatives, as well as a series of environmental phenolic compounds, specically inhibit T3 binding to PDI competitively and suppress the oxidative refolding of the reduced RNase A by PDI. [25][26][27] The competitive replacement of T3 by the targets from PDI may result in decreasing the enzyme activity, erroneous intracellular protein folding, and destroying the physiological functions of PDI. Therefore, the reaction has caused widespread concern, and there are some research teams paying a lot of attention to it.…”