title: Microarray analysis reveals a mechanism of phenolic polybrominated diphenylether toxicity in zebrafish.
abstract: Polybrominated diphenylethers (PBDEs) are ubiquitous in the environment, with the lower brominated congener 2,2',4,4'-tetrabromodiphenylether (BDE47) among the most prevalent. The phenolic PBDE, 6-hydroxy-BDE47 (6-OH-BDE47) is both an important metabolite formed by in vivo metabolism of BDE47 and a natural product produced by marine organisms such as algae. Although this compound has been detected in humans and wildlife, including fish, virtually nothing is known of its in vivo toxicity. Here we report that 6-OH-BDE47 is acutely toxic in developing and adult zebrafish at concentrations in the nanomolar (nM) range. To identify possible mechanisms of toxicity, we used microarray analysis as a diagnostic tool. Zebrafish embryonic fibroblast (PAC2) cells were exposed to 6-OH-BDE47, BDE47, and the methoxylated metabolite 6-MeO-BDE47. These experiments revealed that 6-OH-BDE47 alters the expression of genes involved in proton transport and carbohydrate metabolism. These findings, combined with the acute toxicity, suggested that 6-OH-BDE47 causes disruption of oxidative phosphorylation (OXPHOS).Therefore, we further investigated the effect of 6-OH-BDE47 on OXPHOS in zebrafish mitochondria. Results show unequivocally that this compound is a potent uncoupler of OXPHOS and is an inhibitor of complex II of the electron transport chain. This study provides the first evidence of the in vivo toxicity and an important potential mechanism of toxicity of an environmentally relevant phenolic PBDE of both anthropogenic and natural origin. The results of this study emphasize the need for further investigation on the presence and toxicity of this class of polybrominated compounds.
authors.affiliation: Institute for Environmental Studies and Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands.
authors.forename: Antonius L
authors.initials: AL
authors.lastname: van Boxtel
authors.forename: Jorke H
authors.initials: JH
authors.lastname: Kamstra
authors.forename: Peter H
authors.initials: PH
authors.lastname: Cenijn
authors.forename: Bart
authors.initials: B
authors.lastname: Pieterse
authors.forename: J Marijke
authors.initials: JM
authors.lastname: Wagner
authors.forename: Maartje
authors.initials: M
authors.lastname: Antink
authors.forename: Klaas
authors.initials: K
authors.lastname: Krab
authors.forename: Bart
authors.initials: B
authors.lastname: van der Burg
authors.forename: Göran
authors.initials: G
authors.lastname: Marsh
authors.forename: Abraham
authors.initials: A
authors.lastname: Brouwer
authors.forename: Juliette
authors.initials: J
authors.lastname: Legler
mesh_terms: D000818:Animals; D004987:Ethers; D020411:Oligonucleotide Array Sequence Analysis; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D015027:Zebrafish
chemical_list: D004987:Ethers; D011075:Polybrominated Biphenyls