2018
Strapáčová, Simona; Brenerová, Petra; Krčmář, Pavel; Andersson, Patrik; Ede, Karin I.; Duursen, Majorie B. M.; Berg, Martin; Vondráček, Jan; Machala, Miroslav
Relative effective potencies of dioxin-like compounds in rodent and human lung cell models. Journal Article
In: Toxicology, vol. 404-405, pp. 33–41, 2018, ISSN: 1879-3185 0300-483X, (Place: Ireland).
Abstract | Links | BibTeX | Tags: A549 Cells, Acute/methods, AhR, Animals, Dioxin-like compounds, Dioxins/*toxicity, Dose-Response Relationship, Drug, Endogenous target genes, Female, Humans, Lung epithelial cells, Lung/*drug effects/metabolism/*pathology, Mice, Rats, Relative effective potencies, Rodentia, Species Specificity, Sprague-Dawley, Toxicity Tests
@article{strapacova_relative_2018,
title = {Relative effective potencies of dioxin-like compounds in rodent and human lung cell models.},
author = {Simona Strapáčová and Petra Brenerová and Pavel Krčmář and Patrik Andersson and Karin I. Ede and Majorie B. M. Duursen and Martin Berg and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.tox.2018.05.004},
issn = {1879-3185 0300-483X},
year = {2018},
date = {2018-07-01},
journal = {Toxicology},
volume = {404-405},
pages = {33–41},
abstract = {Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.},
note = {Place: Ireland},
keywords = {A549 Cells, Acute/methods, AhR, Animals, Dioxin-like compounds, Dioxins/*toxicity, Dose-Response Relationship, Drug, Endogenous target genes, Female, Humans, Lung epithelial cells, Lung/*drug effects/metabolism/*pathology, Mice, Rats, Relative effective potencies, Rodentia, Species Specificity, Sprague-Dawley, Toxicity Tests},
pubstate = {published},
tppubtype = {article}
}
Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.
2011
Varel, Urte Lübcke-von; Machala, Miroslav; Ciganek, Miroslav; Neca, Jiri; Pencikova, Katerina; Palkova, Lenka; Vondracek, Jan; Löffler, Ivonne; Streck, Georg; Reifferscheid, Georg; Flückiger-Isler, Sini; Weiss, Jana M.; Lamoree, Marja; Brack, Werner
Polar compounds dominate in vitro effects of sediment extracts. Journal Article
In: Environmental science & technology, vol. 45, no. 6, pp. 2384–2390, 2011, ISSN: 1520-5851 0013-936X, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon/analysis/chemistry, Biological Assay, Chemical Fractionation, Chemical/*analysis/chemistry/toxicity, Endocrine Disruptors/analysis/chemistry/toxicity, Environmental Monitoring, Geologic Sediments/*chemistry, Germany, Humans, Mutagens/analysis/chemistry/toxicity, Prealbumin/analysis/chemistry, Rats, Receptors, Toxicity Tests, Water Pollutants
@article{lubcke-von_varel_polar_2011,
title = {Polar compounds dominate in vitro effects of sediment extracts.},
author = {Urte Lübcke-von Varel and Miroslav Machala and Miroslav Ciganek and Jiri Neca and Katerina Pencikova and Lenka Palkova and Jan Vondracek and Ivonne Löffler and Georg Streck and Georg Reifferscheid and Sini Flückiger-Isler and Jana M. Weiss and Marja Lamoree and Werner Brack},
doi = {10.1021/es103381y},
issn = {1520-5851 0013-936X},
year = {2011},
date = {2011-03-01},
journal = {Environmental science & technology},
volume = {45},
number = {6},
pages = {2384–2390},
abstract = {Sediment extracts from three polluted sites of the river Elbe basin were fractionated using a novel online fractionation procedure. Resulting fractions were screened for mutagenic, aryl hydrocarbon receptor (AhR)-mediated, transthyretin (TTR)-binding, and estrogenic activities and their potency to inhibit gap junctional intercellular communication (GJIC) to compare toxicity patterns and identify priority fractions. Additionally, more than 200 compounds and compound classes were identified using GC-MS/MS, LC-MS/MS, and HPLC-DAD methods. For all investigated end points, major activities were found in polar fractions, which are defined here as fractions containing dominantly compounds with at least one polar functional group. Nonpolar PAH fractions contributed to mutagenic and AhR-mediated activities while inhibition of GJIC and estrogenic and TTR-binding activities were exclusively observed in the polar fractions. Known mutagens in polar fractions included nitro- and dinitro-PAHs, azaarenes, and keto-PAHs, while parent and monomethylated PAHs such as benzo[a]pyrene and benzofluoranthenes were identified in nonpolar fractions. Additionally, for one sample, high AhR-mediated activities were determined in one fraction characterized by PCDD/Fs, PCBs, and PCNs. Estrone, 17β-estradiol, 9H-benz[de]anthracen-7-one, and 4-nonylphenol were identified as possible estrogenic and TTR-binding compounds. Thus, not only nonpolar compounds such as PAHs, PCBs, and PCDD/Fs but also the less characterized and investigated more polar substances should be considered as potent mutagenic, estrogenic, AhR-inducing, TTR-binding, and GJIC-inhibiting components for future studies.},
note = {Place: United States},
keywords = {Animals, Aryl Hydrocarbon/analysis/chemistry, Biological Assay, Chemical Fractionation, Chemical/*analysis/chemistry/toxicity, Endocrine Disruptors/analysis/chemistry/toxicity, Environmental Monitoring, Geologic Sediments/*chemistry, Germany, Humans, Mutagens/analysis/chemistry/toxicity, Prealbumin/analysis/chemistry, Rats, Receptors, Toxicity Tests, Water Pollutants},
pubstate = {published},
tppubtype = {article}
}
Sediment extracts from three polluted sites of the river Elbe basin were fractionated using a novel online fractionation procedure. Resulting fractions were screened for mutagenic, aryl hydrocarbon receptor (AhR)-mediated, transthyretin (TTR)-binding, and estrogenic activities and their potency to inhibit gap junctional intercellular communication (GJIC) to compare toxicity patterns and identify priority fractions. Additionally, more than 200 compounds and compound classes were identified using GC-MS/MS, LC-MS/MS, and HPLC-DAD methods. For all investigated end points, major activities were found in polar fractions, which are defined here as fractions containing dominantly compounds with at least one polar functional group. Nonpolar PAH fractions contributed to mutagenic and AhR-mediated activities while inhibition of GJIC and estrogenic and TTR-binding activities were exclusively observed in the polar fractions. Known mutagens in polar fractions included nitro- and dinitro-PAHs, azaarenes, and keto-PAHs, while parent and monomethylated PAHs such as benzo[a]pyrene and benzofluoranthenes were identified in nonpolar fractions. Additionally, for one sample, high AhR-mediated activities were determined in one fraction characterized by PCDD/Fs, PCBs, and PCNs. Estrone, 17β-estradiol, 9H-benz[de]anthracen-7-one, and 4-nonylphenol were identified as possible estrogenic and TTR-binding compounds. Thus, not only nonpolar compounds such as PAHs, PCBs, and PCDD/Fs but also the less characterized and investigated more polar substances should be considered as potent mutagenic, estrogenic, AhR-inducing, TTR-binding, and GJIC-inhibiting components for future studies.