title: Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells.
abstract: The relative potencies of non-ortho-substituted coplanar polychlorinated biphenyl (PCB) congeners to activate the aryl hydrocarbon receptor (AhR) and to cause the AhR-dependent toxic events are essential for their risk assessment. Since some studies suggested that abundant non-dioxin-like PCB congeners (NDL-PCBs) may alter the AhR activation by PCB mixtures and possibly cause non-additive effects, we evaluated potential suppressive effects of NDL-PCBs on AhR activation, using a series of 24 highly purified NDL-PCBs. We investigated their impact on the model AhR agonist-induced luciferase reporter gene expression in rat hepatoma cells and on induction of CYP1A1/1B1 mRNAs and deregulation of AhR-dependent cell proliferation in rat liver epithelial cells. PCBs 128, 138, and 170 significantly suppressed AhR activation (with IC50 values from 1.4 to 5.6 μM), followed by PCBs 28, 47, 52, and 180; additionally, PCBs 122, 153, and 168 showed low but still significant potency to reduce luciferase activity. Detection of CYP1A1 mRNA levels in liver epithelial cells largely confirmed these results for the most abundant NDL-PCBs, whereas the other AhR-dependent events (CYP1B1 mRNA expression, induction of cell proliferation in confluent cells) were less sensitive to NDL-PCBs, thus indicating a more complex regulation of these endpoints. The present data suggest that some NDL-PCBs could modulate overall dioxin-like effects in complex mixtures.
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Brenerová
authors.affiliation: Institute for Environmental Studies, VU University Amsterdam, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Timo
authors.initials: T
authors.lastname: Hamers
authors.affiliation: Institute for Environmental Studies, VU University Amsterdam, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Jorke H
authors.initials: JH
authors.lastname: Kamstra
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, 62165, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Vondráček
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic.
authors.forename: Simona
authors.initials: S
authors.lastname: Strapáčová
authors.affiliation: Department of Chemistry, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic. machala@vri.cz.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1
keywords: Aryl hydrocarbon receptor; Cytochrome P450; DR-CALUX® assay; Disruption of contact inhibition; NDL-PCBs; Relative effect potency