Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands.
Submitted by Minerva Mercado Feliciano on
Title | Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Mercado-Feliciano, M, Bigsby, RM |
Journal | Environ Health Perspect |
Volume | 116 |
Issue | 10 |
Pagination | 1315-21 |
Date Published | 2008 Oct |
ISSN | 0091-6765 |
Keywords | Animals, Biotransformation, Estrogen Receptor alpha, Genes, Reporter, Halogenated Diphenyl Ethers, Hydroxylation, Ligands, Microsomes, Liver, Phenyl Ethers, Polybrominated Biphenyls, Rats, Recombinant Proteins |
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. |
DOI | 10.1289/ehp.11343 |
Alternate Journal | Environ. Health Perspect. |
PubMed ID | 18941571 |
PubMed Central ID | PMC2569088 |
Grant List | ES013341 / ES / NIEHS NIH HHS / United States ES014367 / ES / NIEHS NIH HHS / United States |