2015
Larsson, Malin; Berg, Martin; Brenerová, Petra; Duursen, Majorie B. M.; Ede, Karin I.; Lohr, Christiane; Luecke-Johansson, Sandra; Machala, Miroslav; Neser, Sylke; Pěnčíková, Kateřina; Poellinger, Lorenz; Schrenk, Dieter; Strapáčová, Simona; Vondráček, Jan; Andersson, Patrik L.
In: Chemical research in toxicology, vol. 28, no. 4, pp. 641–650, 2015, ISSN: 1520-5010 0893-228X, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon/*physiology, Benzofurans/chemistry/*toxicity, Computer Simulation, Dibenzofurans, Humans, In Vitro Techniques, Polychlorinated, Polychlorinated Biphenyls/chemistry/*toxicity, Polychlorinated Dibenzodioxins/*analogs & derivatives/chemistry/toxicity, Quantitative Structure-Activity Relationship, Rats, Receptors, Rodentia
@article{larsson_consensus_2015,
title = {Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells.},
author = {Malin Larsson and Martin Berg and Petra Brenerová and Majorie B. M. Duursen and Karin I. Ede and Christiane Lohr and Sandra Luecke-Johansson and Miroslav Machala and Sylke Neser and Kateřina Pěnčíková and Lorenz Poellinger and Dieter Schrenk and Simona Strapáčová and Jan Vondráček and Patrik L. Andersson},
doi = {10.1021/tx500434j},
issn = {1520-5010 0893-228X},
year = {2015},
date = {2015-04-01},
journal = {Chemical research in toxicology},
volume = {28},
number = {4},
pages = {641–650},
abstract = {Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.},
note = {Place: United States},
keywords = {Animals, Aryl Hydrocarbon/*physiology, Benzofurans/chemistry/*toxicity, Computer Simulation, Dibenzofurans, Humans, In Vitro Techniques, Polychlorinated, Polychlorinated Biphenyls/chemistry/*toxicity, Polychlorinated Dibenzodioxins/*analogs & derivatives/chemistry/toxicity, Quantitative Structure-Activity Relationship, Rats, Receptors, Rodentia},
pubstate = {published},
tppubtype = {article}
}
Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.
2013
Procházková, Jiřina; Kabátková, Markéta; Šmerdová, Lenka; Pacherník, Jiří; Sykorová, Dominika; Kohoutek, Jiří; Šimečková, Pavlína; Hrubá, Eva; Kozubík, Alois; Machala, Miroslav; Vondráček, Jan
Aryl hydrocarbon receptor negatively regulates expression of the plakoglobin gene (jup). Journal Article
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 134, no. 2, pp. 258–270, 2013, ISSN: 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*physiology, Base Sequence, cardiomyocytes., Cell Adhesion, Cell Line, Cell Proliferation, Cloning, desmosomes, dioxin, DNA Primers, Down-Regulation, gamma Catenin/*genetics, Gene Expression Regulation/*physiology, Genetic, Inbred F344, liver progenitor cells, Molecular, plakoglobin, Polychlorinated Dibenzodioxins/pharmacology, Promoter Regions, Rats, Real-Time Polymerase Chain Reaction, Receptors
@article{prochazkova_aryl_2013,
title = {Aryl hydrocarbon receptor negatively regulates expression of the plakoglobin gene (jup).},
author = {Jiřina Procházková and Markéta Kabátková and Lenka Šmerdová and Jiří Pacherník and Dominika Sykorová and Jiří Kohoutek and Pavlína Šimečková and Eva Hrubá and Alois Kozubík and Miroslav Machala and Jan Vondráček},
doi = {10.1093/toxsci/kft110},
issn = {1096-0929},
year = {2013},
date = {2013-08-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {134},
number = {2},
pages = {258–270},
abstract = {Plakoglobin is an important component of intercellular junctions, including both desmosomes and adherens junctions, which is known as a tumor suppressor. Although mutations in the plakoglobin gene (Jup) and/or changes in its protein levels have been observed in various disease states, including cancer progression or cardiovascular defects, the information about endogenous or exogenous stimuli orchestrating Jup expression is limited. Here we show that the aryl hydrocarbon receptor (AhR) may regulate Jup expression in a cell-specific manner. We observed a significant suppressive effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model toxic exogenous activator of the AhR signaling, on Jup expression in a variety of experimental models derived from rodent tissues, including contact-inhibited rat liver progenitor cells (where TCDD induces cell proliferation), rat and mouse hepatoma cell models (where TCDD inhibits cell cycle progression), cardiac cells derived from the mouse embryonic stem cells, or cardiomyocytes isolated from neonatal rat hearts. The small interfering RNA (siRNA)-mediated knockdown of AhR confirmed its role in both basal and TCDD-deregulated Jup expression. The analysis of genomic DNA located textasciitilde2.5kb upstream of rat Jup gene revealed a presence of evolutionarily conserved AhR binding motifs, which were confirmed upon their cloning into luciferase reporter construct. The siRNA-mediated knockdown of Jup expression affected both proliferation and attachment of liver progenitor cells. The present data indicate that the AhR may contribute to negative regulation of Jup gene expression in rodent cellular models, which may affect cell adherence and proliferation.},
note = {Place: United States},
keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*physiology, Base Sequence, cardiomyocytes., Cell Adhesion, Cell Line, Cell Proliferation, Cloning, desmosomes, dioxin, DNA Primers, Down-Regulation, gamma Catenin/*genetics, Gene Expression Regulation/*physiology, Genetic, Inbred F344, liver progenitor cells, Molecular, plakoglobin, Polychlorinated Dibenzodioxins/pharmacology, Promoter Regions, Rats, Real-Time Polymerase Chain Reaction, Receptors},
pubstate = {published},
tppubtype = {article}
}
Plakoglobin is an important component of intercellular junctions, including both desmosomes and adherens junctions, which is known as a tumor suppressor. Although mutations in the plakoglobin gene (Jup) and/or changes in its protein levels have been observed in various disease states, including cancer progression or cardiovascular defects, the information about endogenous or exogenous stimuli orchestrating Jup expression is limited. Here we show that the aryl hydrocarbon receptor (AhR) may regulate Jup expression in a cell-specific manner. We observed a significant suppressive effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model toxic exogenous activator of the AhR signaling, on Jup expression in a variety of experimental models derived from rodent tissues, including contact-inhibited rat liver progenitor cells (where TCDD induces cell proliferation), rat and mouse hepatoma cell models (where TCDD inhibits cell cycle progression), cardiac cells derived from the mouse embryonic stem cells, or cardiomyocytes isolated from neonatal rat hearts. The small interfering RNA (siRNA)-mediated knockdown of AhR confirmed its role in both basal and TCDD-deregulated Jup expression. The analysis of genomic DNA located textasciitilde2.5kb upstream of rat Jup gene revealed a presence of evolutionarily conserved AhR binding motifs, which were confirmed upon their cloning into luciferase reporter construct. The siRNA-mediated knockdown of Jup expression affected both proliferation and attachment of liver progenitor cells. The present data indicate that the AhR may contribute to negative regulation of Jup gene expression in rodent cellular models, which may affect cell adherence and proliferation.