Synthesis of Polybrominated Diphenyl Ethers and Their Capacity to Induce CYP1A by the Ah Receptor Mediated Pathway

Abstract

Polybrominated diphenyl ethers (PBDEs) have become widely distributed as environmental contaminants due to their use as flame retardants. Their structural similarity to other halogenated aromatic pollutants has led to speculation that they might share toxicological properties such as hepatic enzyme induction. In this work we synthesized a number of PBDE congeners, studied their affinity for rat hepatic Ah receptor through competitive binding assays, and determined their ability to induce hepatic cytochrome P-450 enzymes by means of EROD (ethoxyresorufin-O-deethylase) assays in human, rat, chick, and rainbow trout cells. Both pure PBDE congeners and commercial PBDE mixtures had Ah receptor binding affinities 10(-2)-10(-5) times that of 2,3,7,8-tetrachlorodibenzo-p-dioxin. In contrast with polychlorinated biphenyls, Ah receptor binding affinities of PBDEs could not be related to the planarity of the molecule, possibly because the large size of the bromine atoms expands the Ah receptor's binding site. EROD activities of the PBDE congeners followed a similar rank order in all cells. Some congeners, notably PBDE 85, did not follow the usual trend in which strength of Ah receptor binding affinity paralleled P-450 induction potency. Use of the gel retardation assay with a synthetic oligonucleotide indicated that in these cases the liganded Ah receptor failed to bind to the DNA recognition sequence.

Primary cultured cells as sensitive in vitro model for assessment of toxicants-comparison to hepatocytes and gill epithelia

“…There was no EROD induction by DE71 in both cultured gill epithelia and hepatocytes in the present study, although a weak EROD induction was reported in BDE-77, 100, 153, and 183 in mammalian cell lines (Chen et al, 2001;Behnisch et al, 2003) and in primary cultured rat hepatocytes (Rattus norvegicus) (Chen et al, 2001;Chen and Bunce, 2003). Our results are consistent with previous experiments in primary cultured carp (Cyprinus carpio) hepatocytes (Kuiper et al, 2004) and monkey (Macaca fascicularis) hepatocytes (Peters et al, 2006).…”

Bioconcentration and metabolism of decabromodiphenyl ether (BDE-209) result in thyroid endocrine disruption in zebrafish larvae

“…Szabo et al (2009) indicated that UGT-T4 is not the most sensitive marker for DE-71, and the regulation of UGT to THs is thought to be nuclear receptor specific. Since BDE-209 has a very limited potential to activate the transcriptional factor, aryl hydrocarbon receptor (AhR) (Chen et al, 2001;Villeneuve et al, 2002), the decreased T4 levels in our study may not be directly related to the regulation of UGT. Therefore, the mechanistic relationships between metabolic genes and THs upon BDE-209 exposure require further study.…”

Separation of polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins and dibenzo-furans in environmental samples using silica gel and florisil fractionation chromatography

“…Polychlorinated biphenyl (PCBs) and polybrominated diphenyl ethers (PBDEs) have been manufactured in large quantities and are contained in many industrial and consumer products [1,2]. It was reported that both PCBs and PBDEs possess dioxin-like activity, and all of them are toxic, endocrine disrupting, and probably carcinogenic [3,4]. Because all these three groups of pollutants are ubiquitous, it is likely that they co-exist in most environmental matrices [5][6][7][8][9].…”