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

Minerva Mercado-Feliciano, Robert Bigsby

Research output: Contribution to journalArticle

76 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)1315-1321
Number of pages7
JournalEnvironmental Health Perspectives
Volume116
Issue number10
DOIs
StatePublished - 2008

Fingerprint

Halogenated Diphenyl Ethers
Estrogen Receptors
Ligands
Reporter Genes
pentabromodiphenyl ether
Endocrine Disruptors
Liver Microsomes
Luciferases
Estradiol
Cultured Cells
Estrogens

Keywords

  • Cytochrome P450
  • DE-71
  • Endocrine disruptors
  • ERE-luciferase
  • Estrogens
  • Mice
  • Ovariectomized
  • PBDEs
  • Polybrominated diphenyl ethers

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

Cite this

Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 Are weak estrogen receptor-α ligands. / Mercado-Feliciano, Minerva; Bigsby, Robert.

In: Environmental Health Perspectives, Vol. 116, No. 10, 2008, p. 1315-1321.

Research output: Contribution to journalArticle

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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-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.",
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T1 - Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 Are weak estrogen receptor-α ligands

AU - Mercado-Feliciano, Minerva

AU - Bigsby, Robert

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N2 - 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.

AB - 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.

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KW - Ovariectomized

KW - PBDEs

KW - Polybrominated diphenyl ethers

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