Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener.
Polybrominated diphenyl ethers (PBDEs) are a class of polyhalogenated aromatic compounds commercially used as fire retardants in consumer products. These compounds have been shown to decrease thyroid hormone concentrations in rodents after acute exposures. This study examines the ability of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) to decrease circulating thyroid hormone concentrations and pairs this with BDE 47-induced effects on genes involved in thyroid hormone homeostasis. Female C57BL/6 mice (9 weeks old) were orally administered 3, 10, or 100 mg/kg/day of BDE 47 for 4 days. Animals were euthanized 24 h after the final dose (day 5) and liver, kidney, and serum were collected for analysis. BDE 47 caused a significant 43% decrease at 100 mg/kg/day in serum total thyroxine (T(4)) concentrations. There was no increase in hepatic T(4)-glucuronidation activity, but significant increases in hepatic Ugt1a1, Ugt1a7, and Ugt2b5 mRNA expression accompany significant decreases in T(4) concentrations at 100 mg/kg/day of BDE 47. Induction of PROD activity occurred at the lowest dose (3 mg/kg/day). Cyp2b10 mRNA expression also increased significantly at 10 and 100 mg/kg/day. These key findings show that BDE activates the nuclear receptor, CAR. Decreases in Mdr1a mRNA expression also occurred at the lowest dose administered (3 mg/kg/day BDE 47). BDE 47 exposure also decreased hepatic transthyretin and monocarboxylate transporter 8 (Mct8) mRNA expression, suggesting that while induction of UGTs may be partly responsible for T(4) decreases, other mechanisms are also involved. No effects were seen in the kidney. We conclude that changes in hepatic UGTs and transporters may be involved in decreases in circulating T(4) following BDE 47 exposure.
Richardson
Vicki M
VM
US EPA, ORD, NHEERL, ETD 109 TW Alexander Dr. MD B143-01 Research Triangle Park, NC 27711, USA. richardson.vicki@epa.gov
Staskal
Daniele F
DF
Ross
David G
DG
Diliberto
Janet J
JJ
DeVito
Michael J
MJ
Birnbaum
Linda S
LS
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction; D005260:Female; D005411:Flame Retardants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D027501:Monocarboxylic Acid Transporters; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D027981:Symporters; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013974:Thyroxine / Q000097:blood*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D011075:Polybrominated Biphenyls; D011228:Prealbumin; D012333:RNA, Messenger; C484257:Slc16a2 protein, mouse; D027981:Symporters; C511295:2,2',4,4'-tetrabromodiphenyl ether; C095122:multidrug resistance protein 3; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D019362:Cytochrome P-450 CYP2B1; D000072467:Cytochrome P450 Family 2; D014453:Glucuronosyltransferase; D011494:Protein Kinases; D013974:Thyroxine