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 language | English |
|---|---|
| Pages (from-to) | 1315-1321 |
| Number of pages | 7 |
| Journal | Environmental Health Perspectives |
| Volume | 116 |
| Issue number | 10 |
| DOIs | |
| State | Published - 2008 |
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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 journal › Article
}
TY - JOUR
T1 - Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 Are weak estrogen receptor-α ligands
AU - Mercado-Feliciano, Minerva
AU - Bigsby, Robert
PY - 2008
Y1 - 2008
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.
KW - Cytochrome P450
KW - DE-71
KW - Endocrine disruptors
KW - ERE-luciferase
KW - Estrogens
KW - Mice
KW - Ovariectomized
KW - PBDEs
KW - Polybrominated diphenyl ethers
UR - http://www.scopus.com/inward/record.url?scp=55949090982&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55949090982&partnerID=8YFLogxK
U2 - 10.1289/ehp.11343
DO - 10.1289/ehp.11343
M3 - Article
VL - 116
SP - 1315
EP - 1321
JO - Environmental Health Perspectives
JF - Environmental Health Perspectives
SN - 0091-6765
IS - 10
ER -