Latest Publications

@article{pencikova_vitro_2018,

title = {In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion.},

author = {Kateřina Pěnčíková and Lucie Svržková and Simona Strapáčová and Jiří Neča and Iveta Bartoňková and Zdeněk Dvořák and Martina Hýžďalová and Jakub Pivnička and Lenka Pálková and Hans-Joachim Lehmler and Xueshu Li and Jan Vondráček and Miroslav Machala},

doi = {10.1016/j.envpol.2018.02.067},

issn = {1873-6424 0269-7491},

year  = {2018},

date = {2018-06-01},

journal = {Environmental pollution (Barking, Essex : 1987)},

volume = {237},

pages = {473–486},

abstract = {The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.},

note = {Place: England},

keywords = {Air Pollutants/*toxicity, Airborne polychlorinated biphenyls, Cell Line, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/metabolism, Endocrine disruption, Endocrine Disruptors/metabolism/*toxicity, Epithelial Cells/drug effects, Humans, HydroxyLated PCBs, Hydroxylation, Metabolism of xenobiotics, Neoplasms/metabolism, Polychlorinated Biphenyls/metabolism/*toxicity, Pregnane X receptor, Receptors, Signal Transduction/drug effects, Steroid/metabolism, Tumor promotion},

pubstate = {published},

tppubtype = {article}

}

@article{umannova_tumor_2007,

title = {Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells.},

author = {Lenka Umannová and Jirina Zatloukalová and Miroslav Machala and Pavel Krcmár and Zuzana Májková and Bernhard Hennig and Alois Kozubík and Jan Vondrácek},

doi = {10.1093/toxsci/kfm149},

issn = {1096-6080 1096-0929},

year  = {2007},

date = {2007-09-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {99},

number = {1},

pages = {79–89},

abstract = {Various liver diseases lead to an extensive inflammatory response and release of a number of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). This cytokine is known to play a major role in liver regeneration as well as in carcinogenesis. We investigated possible interactions of TNF-alpha with ligands of the aryl hydrocarbon receptor (AhR) and known liver carcinogens, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and coplanar 3,3',4,4',5-pentachlorobiphenyl (PCB 126). These compounds have been previously found to disrupt cell cycle control in contact-inhibited rat liver WB-F344 cells, an in vitro model of adult liver progenitor cells. TNF-alpha itself had no significant effect on the proliferation/apoptosis ratio in the WB-F344 cell line. However, it significantly potentiated proliferative effects of low picomolar range doses of both TCDD and PCB 126, leading to an increase in cell numbers, as well as an increased percentage of cells entering the S-phase of the cell cycle. The combination of TNF-alpha with low concentrations of AhR ligands increased both messenger RNA (mRNA) and protein levels of cyclin A, a principle cyclin involved in disruption of contact inhibition. TNF-alpha temporarily inhibited AhR-dependent induction of cytochrome P450 1A1 (CYP1A1). In contrast, TNF-alpha significantly enhanced induction of CYP1B1 at both mRNA and protein levels, by a mechanism, which was independent of nuclear factor-kappaB activation. These results suggest that TNF-alpha can significantly amplify effects of AhR ligands on deregulation of cell proliferation control, as well as on expression of CYP1B1, which is involved in metabolic activation of a number of mutagenic compounds.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon Hydroxylases/genetics/*metabolism, Aryl Hydrocarbon/*drug effects/metabolism, Carcinogens/metabolism/toxicity, Cell Proliferation/drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Enzymologic/*drug effects, Epithelial Cells/drug effects/enzymology, Gene Expression Regulation, Inbred F344, Ligands, Liver/cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Polychlorinated Dibenzodioxins/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology, Tumor Necrosis Factor-alpha/*pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_aryl_2005,

title = {Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.},

author = {Jan Vondrácek and Miroslav Machala and Vítezslav Bryja and Katerina Chramostová and Pavel Krcmár and Cornelia Dietrich and Ales Hampl and Alois Kozubík},

doi = {10.1093/toxsci/kfi009},

issn = {1096-6080 1096-0929},

year  = {2005},

date = {2005-01-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {83},

number = {1},

pages = {53–63},

abstract = {Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Proliferation/*drug effects, Cyclin A/biosynthesis, Cyclin D2, Cyclin-Dependent Kinases/biosynthesis, Cyclins/biosynthesis, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Hydroxylation, Liver/*cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Up-Regulation},

pubstate = {published},

tppubtype = {article}

}