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-α (ER-α). Methods: We tested estrogenicity using two assays: ³H-estradiol (³H-E₂) displacement from recombinant ER-α, 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-α, but all six of the OH-PBDE metabolites did. para-Hydroxylated metabolites displayed a 10- to 30-fold higher affinity for ER-α 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-α, 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-α activation.