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Nuclear hormone receptor activity of polybrominated diphenyl ethers and their hydroxylated and methoxylated metabolites in transactivation assays using Chinese hamster ovary cells.

Kojima H, Takeuchi S, Uramaru N, Sugihara K, Yoshida T, Kitamura S - Environ. Health Perspect. (2009)

Bottom Line: An increasing number of studies are reporting the existence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (HO) and methoxylated (MeO) metabolites in the environment and in tissues from wildlife and humans.Our aim was to characterize and compare the agonistic and antagonistic activities of principle PBDE congeners and their HO and MeO metabolites against human nuclear hormone receptors.Taken together, these results suggest that PBDEs and their metabolites might have multiple endocrine-disrupting effects via nuclear hormone receptors, and para-HO-PBDEs, in particular, possess more potent receptor activities compared with those of the parent PBDEs and corresponding para-MeO-PBDEs.

View Article: PubMed Central - PubMed

Affiliation: Hokkaido Institute of Public Health, Sapporo, Japan. kojima@iph.pref.hokkaido.jp

ABSTRACT

Background: An increasing number of studies are reporting the existence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (HO) and methoxylated (MeO) metabolites in the environment and in tissues from wildlife and humans.

Objective: Our aim was to characterize and compare the agonistic and antagonistic activities of principle PBDE congeners and their HO and MeO metabolites against human nuclear hormone receptors.

Methods: We tested the hormone receptor activities of estrogen receptor alpha (ERalpha), ERbeta, androgen receptor (AR), glucocorticoid receptor (GR), thyroid hormone receptor alpha(1) (TRalpha(1)), and TRbeta(1) against PBDE congeners BDEs 15, 28, 47, 85, 99, 100, 153, and 209, four para-HO-PBDEs, and four para-MeO-PBDEs by highly sensitive reporter gene assays using Chinese hamster ovary cells.

Results: Of the 16 compounds tested, 6 and 2 showed agonistic activities in the ERalpha and ERbeta assays, respectively, and 6 and 6 showed antagonistic activities in these assays. 4'-HO-BDE-17 showed the most potent estrogenic activity via ERalpha/beta, and 4'-HO-BDE-49 showed the most potent anti estrogenic activity via ERalpha/beta. In the AR assay, 13 compounds showed antagonistic activity, with 4'-HO-BDE-17 in particular inhibiting AR-mediated transcriptional activity at low concentrations in the order of 10(-8) M. In the GR assay, seven compounds, including two HO-PBDEs and two MeO-PBDEs, showed weak antagonistic activity. In the TRalpha(1) and TRbeta(1) assays, only 4-HO-BDE-90 showed weak antagonistic activity.

Conclusions: Taken together, these results suggest that PBDEs and their metabolites might have multiple endocrine-disrupting effects via nuclear hormone receptors, and para-HO-PBDEs, in particular, possess more potent receptor activities compared with those of the parent PBDEs and corresponding para-MeO-PBDEs.

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Dose–response curves for E2 (A), DHT (B), HC (C), and T3 (D) obtained from the ERα/β, AR, GR, and TRα1/β1 transactivation assays, respectively, of CHO cells transiently transfected with an expression plasmid for hERα/β, hAR, hGR, and hTRα1/β1 as well as a reporter-responsive firefly luciferase plasmid and a constitutively active β-galactosidase expression plasmid. See “Methods and Methods” for details. Values represent the mean ± SD of three independent experiments and are presented as the mean n-fold induction over the vehicle control.
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f2-ehp-117-1210: Dose–response curves for E2 (A), DHT (B), HC (C), and T3 (D) obtained from the ERα/β, AR, GR, and TRα1/β1 transactivation assays, respectively, of CHO cells transiently transfected with an expression plasmid for hERα/β, hAR, hGR, and hTRα1/β1 as well as a reporter-responsive firefly luciferase plasmid and a constitutively active β-galactosidase expression plasmid. See “Methods and Methods” for details. Values represent the mean ± SD of three independent experiments and are presented as the mean n-fold induction over the vehicle control.

Mentions: Figure 2A shows the dose–response curve of E2 from the ERα assay. From the dose–response curve, we estimated the REC20 value of E2 for ERα to be 2.5 × 10−12 M. As shown in Figure 3A, we found that 6 of the 16 compounds tested induced estrogenic activity greater than the 20% of the maximum activity of E2 in the ERα assay. The REC20 values of the compounds with ERα agonistic activity are described in Table 1. The relative potencies of their ERα agonistic activities descended in the following order: 4′-HO-BDE-17 ≫ 4′-MeO-BDE-17, 4-HO-BDE-42 > BDE-100 > BDE-47 > BDE-28. The estrogenic activity via ERα of 4′-HO-BDE-17 was about 100,000-fold lower than that of E2.


Nuclear hormone receptor activity of polybrominated diphenyl ethers and their hydroxylated and methoxylated metabolites in transactivation assays using Chinese hamster ovary cells.

Kojima H, Takeuchi S, Uramaru N, Sugihara K, Yoshida T, Kitamura S - Environ. Health Perspect. (2009)

Dose–response curves for E2 (A), DHT (B), HC (C), and T3 (D) obtained from the ERα/β, AR, GR, and TRα1/β1 transactivation assays, respectively, of CHO cells transiently transfected with an expression plasmid for hERα/β, hAR, hGR, and hTRα1/β1 as well as a reporter-responsive firefly luciferase plasmid and a constitutively active β-galactosidase expression plasmid. See “Methods and Methods” for details. Values represent the mean ± SD of three independent experiments and are presented as the mean n-fold induction over the vehicle control.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2721863&req=5

f2-ehp-117-1210: Dose–response curves for E2 (A), DHT (B), HC (C), and T3 (D) obtained from the ERα/β, AR, GR, and TRα1/β1 transactivation assays, respectively, of CHO cells transiently transfected with an expression plasmid for hERα/β, hAR, hGR, and hTRα1/β1 as well as a reporter-responsive firefly luciferase plasmid and a constitutively active β-galactosidase expression plasmid. See “Methods and Methods” for details. Values represent the mean ± SD of three independent experiments and are presented as the mean n-fold induction over the vehicle control.
Mentions: Figure 2A shows the dose–response curve of E2 from the ERα assay. From the dose–response curve, we estimated the REC20 value of E2 for ERα to be 2.5 × 10−12 M. As shown in Figure 3A, we found that 6 of the 16 compounds tested induced estrogenic activity greater than the 20% of the maximum activity of E2 in the ERα assay. The REC20 values of the compounds with ERα agonistic activity are described in Table 1. The relative potencies of their ERα agonistic activities descended in the following order: 4′-HO-BDE-17 ≫ 4′-MeO-BDE-17, 4-HO-BDE-42 > BDE-100 > BDE-47 > BDE-28. The estrogenic activity via ERα of 4′-HO-BDE-17 was about 100,000-fold lower than that of E2.

Bottom Line: An increasing number of studies are reporting the existence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (HO) and methoxylated (MeO) metabolites in the environment and in tissues from wildlife and humans.Our aim was to characterize and compare the agonistic and antagonistic activities of principle PBDE congeners and their HO and MeO metabolites against human nuclear hormone receptors.Taken together, these results suggest that PBDEs and their metabolites might have multiple endocrine-disrupting effects via nuclear hormone receptors, and para-HO-PBDEs, in particular, possess more potent receptor activities compared with those of the parent PBDEs and corresponding para-MeO-PBDEs.

View Article: PubMed Central - PubMed

Affiliation: Hokkaido Institute of Public Health, Sapporo, Japan. kojima@iph.pref.hokkaido.jp

ABSTRACT

Background: An increasing number of studies are reporting the existence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (HO) and methoxylated (MeO) metabolites in the environment and in tissues from wildlife and humans.

Objective: Our aim was to characterize and compare the agonistic and antagonistic activities of principle PBDE congeners and their HO and MeO metabolites against human nuclear hormone receptors.

Methods: We tested the hormone receptor activities of estrogen receptor alpha (ERalpha), ERbeta, androgen receptor (AR), glucocorticoid receptor (GR), thyroid hormone receptor alpha(1) (TRalpha(1)), and TRbeta(1) against PBDE congeners BDEs 15, 28, 47, 85, 99, 100, 153, and 209, four para-HO-PBDEs, and four para-MeO-PBDEs by highly sensitive reporter gene assays using Chinese hamster ovary cells.

Results: Of the 16 compounds tested, 6 and 2 showed agonistic activities in the ERalpha and ERbeta assays, respectively, and 6 and 6 showed antagonistic activities in these assays. 4'-HO-BDE-17 showed the most potent estrogenic activity via ERalpha/beta, and 4'-HO-BDE-49 showed the most potent anti estrogenic activity via ERalpha/beta. In the AR assay, 13 compounds showed antagonistic activity, with 4'-HO-BDE-17 in particular inhibiting AR-mediated transcriptional activity at low concentrations in the order of 10(-8) M. In the GR assay, seven compounds, including two HO-PBDEs and two MeO-PBDEs, showed weak antagonistic activity. In the TRalpha(1) and TRbeta(1) assays, only 4-HO-BDE-90 showed weak antagonistic activity.

Conclusions: Taken together, these results suggest that PBDEs and their metabolites might have multiple endocrine-disrupting effects via nuclear hormone receptors, and para-HO-PBDEs, in particular, possess more potent receptor activities compared with those of the parent PBDEs and corresponding para-MeO-PBDEs.

Show MeSH
Related in: MedlinePlus