title: Antagonism of TCDD-induced ethoxyresorufin-O-deethylation activity by polybrominated diphenyl ethers (PBDEs) in primary cynomolgus monkey (Macaca fascicularis) hepatocytes.
abstract: Polybrominated diphenyl ethers (PBDEs) are widespread environmental pollutants, and the levels of certain congeners have been increasing in biota and abiota in recent decades. Some PBDEs are lipophilic and persistent, resulting in bioaccumulation in the environment. Their structural similarity to other polyhalogenated aromatic hydrocarbons (PHAHs) such as polychlorinated biphenyls (PCBs) has raised concerns that PBDEs might act as agonists for the aryl hydrocarbon receptor (AhR). Recent studies in our laboratory with human and rat cell lines indicated no AhR mediated CYP1A1 induction for PBDEs. However, an earlier in vitro study by Van der Burght et al. (1999) [Van der Burght, A.S., Clijsters, P.J., Horbach, G.J., Andersson, P.L., Tysklind, M., van den Berg, M., 1999. Structure-dependent induction of CYP1A by polychlorinated biphenyls in hepatocytes of cynomolgus monkeys (Macaca fascicularis). Toxicol. Appl. Pharmacol. 155, 13-23] indicated that in cynomolgus monkey (M. fascicularis) hepatocytes PCBs with a non-planar configuration could induce CYP1A. As PBDEs show a structural similarity with non-planar (ortho substituted) PCBs, our present study focused on the possible CYP1A induction by PBDEs (BDE-47, -99, -100, -153, -154, -183, and -77) in individual preparations (n=4) of primary hepatocytes of cynomolgus monkeys (M. fascicularis). 7-Ethoxyresorufin-O-deethylase (EROD) was used as a marker for CYP1A-mediated catalytic activity. Cells were exposed for 48 h to various PBDE concentrations (0.01-10 microM), positive controls 2,3,7,8-TCDD (0.001-2.5 nM) and PCB-126 (0.01-10nM), and negative control (DMSO vehicle alone). No statistically significant induction of CYP1A was observed in the hepatocytes after 48 h of exposure to all environmentally relevant PBDEs. After exposing hepatocytes to PBDEs in combination with TCDD, a concentration-dependent decrease in TCDD-induced EROD activity was observed. All PBDEs tested showed a similar reduction in each of four experiments, though quantitative differences were observed. The observed antagonism of TCDD-induced EROD activity by PBDEs occurred in both male (n=3) and female (n=1) hepatocytes and was not due to catalytic inhibition of EROD activity or cytotoxicity. However, based on the results of this study we do not expect these antagonistic effects of PBDEs on CYP1A induction at environmental relevant levels, since these in vitro interactive effects with TCDD were observed only at relatively high concentrations that are normally not seen, e.g. in the human body.
authors.affiliation: Institute for Risk Assessment Sciences (IRAS), Utrecht University, Yalelaan 2, PO Box 80176, 3508 TD Utrecht, The Netherlands. L.peters@iras.uu.nl
authors.forename: A K
authors.initials: AK
authors.lastname: Peters
authors.forename: J T
authors.initials: JT
authors.lastname: Sanderson
authors.forename: A
authors.initials: A
authors.lastname: Bergman
authors.forename: M
authors.initials: M
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D005411:Flame Retardants / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*
chemical_list: D005411:Flame Retardants; D011075:Polybrominated Biphenyls; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1