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Environ Health Perspect. 2008 Oct;116(10):1315-21. doi: 10.1289/ehp.11343. Epub 2008 May 27.

Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands.

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  • 1Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5121, USA.

Abstract

BACKGROUND:

Polybrominated diphenyl ethers (PBDEs) are widely found in the environment and are suspected endocrine disruptors. We previously identified six hydroxylated metabolites of PBDE (OH-PBDEs) in treated mice.

OBJECTIVE:

We tested the hypothesis that OH-PBDEs would interact with and alter activity of estrogen receptor-alpha (ER-alpha).

METHODS:

We tested estrogenicity using two assays: 3H-estradiol (3H-E2) displacement from recombinant ER-alpha and induction of reporter gene (ERE-luciferase) in cultured cells. We incubated the PBDE mixture DE-71 with rat liver microsomes and tested the resultant metabolite mixture for estrogenic activity. We also determined relative estrogenic potential of individual hydroxylated PBDE congeners.

RESULTS:

Reporter gene activity was increased by DE-71 that had been subjected to microsomal metabolism. DE-71 did not displace E2 from ER-alpha, but all six of the OH-PBDE metabolites did. para-Hydroxylated metabolites displayed a 10- to 30-fold higher affinity for ER-alpha compared with ortho-hydroxylated PBDEs, and one produced a maximal effect 30% higher than that produced by E2. Coadministration of E2 and DE-71, or certain of its metabolites, yielded reporter activity greater than either chemical alone. Two ortho-OH-PBDEs were antiestrogenic in the reporter assay.

CONCLUSIONS:

The observations--that the DE-71 mixture did not displace 3H-E2 from ER-alpha while the hydroxylated metabolites did-suggest that the weak estrogenic effects of DE-71 are due to metabolic activation of individual congeners. However, the behavior of DE-71 and its metabolites, when co-administered with E2, suggest a secondary, undetermined mechanism from classical ER-alpha activation.

KEYWORDS:

DE-71; ERE-luciferase; PBDEs; cytochrome P450; endocrine disruptors; estrogens; mice; ovariectomized; polybrominated diphenyl ethers

PMID:
18941571
[PubMed - indexed for MEDLINE]
PMCID:
PMC2569088
Free PMC Article
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