Mechanisms of Toxicity of Polybrominated Diphenyl Ethers

Abstract

Lower molecular weight polybrominated diphenyl ethers (PBDEs) including 2,2',4,4'-tetraBDE (BDE47), 2,2',4,4',5-pentaBDE (BDE99), and 2,2',4,4',5,5'-hexaBDE (BDE153) have accumulated in the abiotic and biotic environment and are detected in human tissues and fluids. All three PBDEs are components of commercial pentaBDE mixtures primarily used as flame retardants in polyurethane foams. PentaBDE mixtures are both dioxin- and phenobarbital-like enzyme inducers and cause toxicity in rodents. Therefore, studies were designed to correlate biological effects with specific components of a pentaBDE mixture, as well as search for congener-specific differences in metabolic fates that could influence their toxic potentials. Quantitative RT-PCR analysis demonstrated that BDE47, BDE99, and BDE153 had little or no ability to up-regulate CYP1A1 gene expression in rat liver; therefore, are not dioxin-like. GC-MS analysis indicated that polybrominated dibenzodioxins and furans (PBDD⁄Fs) were present in the pentaBDE mixture and individual PBDEs. PBDD⁄Fs appear to be responsible for dioxin-like effects in rodents exposed to pentaBDE mixtures. Conversely, PBDEs up-regulated CYP2B and CYP3A gene expression in rats within the same order of magnitude as noncoplanar PCB153; therefore, are apparent CAR and PXR agonists. 14C-Labeled BDE47, BDE99, or BDE153 were readily absorbed, retained in lipid, accumulated in tissues, and were slowly excreted. BDE99 was metabolized to the greatest extent; whereas, BDE153 underwent minimal metabolism. BDE47 and BDE99 apparently induced their own metabolism following repeated exposure and are probable substrates of CYP2B. Metabolism of BDE47 and BDE99 resulted in formation of reactive intermediates in rats. Conjugates derived from arene oxides are excreted in urine and bile of BDE47-treated rats and conjugated bromophenols are excreted in urine as a result of oxidative cleavage of the molecule. BDE99 forms reactive metabolite(s) capable of binding liver protein. In summary, these studies have shown that toxic response in rodents exposed to pentaBDE mixtures may correlate with PBDE induction of CYP2B and CYP3A, congener-specific formation of reactive metabolites, and the presence of contaminants capable of inducing CYP1A1.