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

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: H-3-estradiol (H-3-E-2) 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 E-2 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 E-2. Coadministration of E-2 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 H-3-E-2 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 E-2, suggest a secondary, undetermined mechanism from classical ER-alpha activation.