A technical mixture of 2,2',4,4'-tetrabromo diphenyl ether (BDE47) and brominated furans triggers aryl hydrocarbon receptor (AhR) mediated gene expression and toxicity.
Polybrominated diphenyl ethers (PBDE) are found as ubiquitous contaminants in the environment, e.g., in sediments and biota as well as in human blood samples and mother's milk. PBDEs are neuro- and developmental toxins, disturb the endocrine system and some are even carcinogenic. Structural similarities of PBDEs with dioxin-like compounds, e.g., 2,3,7,8-tetrachloro-dibenzodioxin (TCDD), have raised concern about a possible "dioxin-like" action of PBDEs. TCDD exerts its toxicity via binding to and activation of the aryl hydrocarbon receptor (AhR). AhR ligands are in contrast to PBDEs usually coplanar compounds. Thus, PBDEs are not likely to be strong AhR agonists. The aim of this study was to analyze the effects of the most abundant PBDE congener, 2,2',4,4'-tetrabromo diphenyl ether (BDE47), on AhR activity and signaling. Initially, we measured cytochrome P450 1A1 (Cyp1A1) induction as a readout for AhR activation by BDE47. Low grade purified BDE47 increased CYP1A1 levels in transformed and primary rat hepatocytes and human hepatoma cells. Chemical analysis of the BDE47 sample identified trace contaminations with brominated furans such as 2,3,7,8-tetrabromo dibenzodioxin (TBDF), which most likely were responsible for the observed activation of AhR. Subsequently, the BDE47 mixture was studied for its effect on AhR mediated toxicity and global gene expression. Indeed, in rat hepatoma cells and in zebrafish embryos the BDE47 mixture provoked changes in gene expression and toxicity similar to known AhR agonists. In addition to the dioxin-like actions, the BDE47 sample enhanced Cyp2B and Cyp3A expression suggesting that commercial PBDE mixtures, which also often contain brominated furans, may disturb cellular homeostasis at multiple levels.
Wahl
M
M
Institute of Toxicology and Genetics (ITG), Research Center Karlsruhe (FZK), Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany.
Lahni
B
B
Guenther
R
R
Kuch
B
B
Yang
L
L
Straehle
U
U
Strack
S
S
Weiss
C
C
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055768:Halogenated Diphenyl Ethers; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish
D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D018336:Receptors, Aryl Hydrocarbon; C511295:2,2',4,4'-tetrabromodiphenyl ether; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A