EPA Science Inventory

Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes

Citation:

Sueyoshi, T., L. Li, H. Wang, R. Moore, P. Kodavanti, H. Lehmler, M. Negishi, AND L. Birnbaum. Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes. TOXICOLOGICAL SCIENCES. Society of Toxicology, 137(2):292-302, (2014).

Description:

Polybrominated diphenyl ether BDE-47 (2,2’,4,4’-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car-/- and Pxr-/- mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor CAR. In mouse livers, CAR, not PXR, was responsible for the induction of CYP2B1O mRNA by BDE-47. In human primary hepatocytes, BDE-47 was as effective as the classic CAR activator phenobarbital at translocating YFP-tagged human CAR from the cytoplasm to the nucleus, inducing CYP2B6 and CYP3A4 mRNAs. BDE-47 activated human CAR in a manner akin to the human CAR ligand CITCO in Luc-reporter assays using Huh-7 cells. In contrast, mouse CAR was not potently activated by BDE-47 in the same reporter assays. Furthermore, human PXR was effectively activated by BDE-47 while mouse PXR was not in Luc-reporter assays. Thus, these results indicate that BDE-47 indirectly activates mouse CAR like phenobarbital does, while it is a ligand for human CAR and PXR.

Purpose/Objective:

Polybrominated diphenyl ether BDE-47 (2,2’,4,4’-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car-/- and Pxr-/- mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor CAR.

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Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 04/02/2014
Completion Date: 04/02/2014
Record Last Revised: 08/13/2014
Record Created: 04/02/2014
Record Released: 04/02/2014
OMB Category: Other
Record ID: 272397

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

TOXICOLOGY ASSESSMENT DIVISION

NEUROTOXICOLOGY BRANCH