Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression.
Polybrominated diphenyl ethers (PBDEs) accumulate in the environment and in humans. PBDEs are developmental neurotoxicants, disturb the endocrine system and induce tumors in rodents. However, underlying mechanisms of PBDE toxicity are still insufficiently understood. Some reports demonstrated activation but also inhibition of the aryl hydrocarbon receptor (AhR) by PBDEs based on expression of its target gene cyp1A1. In the present study, we used different PBDE congeners (BDE47, 99, 153 and 209) and analyzed their effects on AhR signaling in various cell lines and zebrafish embryos. Furthermore, we performed microarray experiments in rat hepatoma cells to compare changes in gene expression induced by either BDE47 or the AhR agonist 2,3,7,8-tetrabromo-dibenzofuran (TBDF). PBDEs did not activate but rather inhibited AhR signaling and specifically induced malformations in zebrafish embryos, which differ from those provoked by AhR agonists. Furthermore, BDE47 and TBDF differentially regulated global gene expression in hepatoma cells. Hence, PBDEs and AhR agonists trigger different toxicity and target gene expression. Several novel target genes of BDE47 and TBDF were identified and verified by RT-PCR. TBDF induced expression of the transcriptional regulators Sim2 and RevErbbeta whereas BDE47 specifically deregulated expression of two subunits of the cytochrome c oxidase complex, cox6a2 and cox4i2, which might be linked to its toxicity.
Wahl
M
M
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Campus North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
Guenther
R
R
Yang
L
L
Bergman
A
A
Straehle
U
U
Strack
S
S
Weiss
C
C
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D015027:Zebrafish / Q000196:embryology
D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1