2024
Hýžďalová, Martina; Procházková, Jiřina; Straková, Nicol; Pěnčíková, Kateřina; Strapáčová, Simona; Slováčková, Jana; Kajabová, Simona; Líbalová, Helena; Topinka, Jan; Kabátková, Markéta; Vondráček, Jan; Mollerup, Steen; Machala, Miroslav
In: Environmental toxicology and pharmacology, vol. 107, pp. 104424, 2024, ISSN: 1872-7077 1382-6689, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Benzo(a)pyrene/toxicity, *Epithelial Cells/metabolism, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Benzo[a]pyrene, DNA Damage, Epithelial-Mesenchymal Transition, Human bronchial epithelial cells, Humans, Ligands, Receptors
@article{hyzdalova_transcriptional_2024,
title = {Transcriptional and phenotypical alterations associated with a gradual benzo[a]pyrene-induced transition of human bronchial epithelial cells into mesenchymal-like cells.},
author = {Martina Hýžďalová and Jiřina Procházková and Nicol Straková and Kateřina Pěnčíková and Simona Strapáčová and Jana Slováčková and Simona Kajabová and Helena Líbalová and Jan Topinka and Markéta Kabátková and Jan Vondráček and Steen Mollerup and Miroslav Machala},
doi = {10.1016/j.etap.2024.104424},
issn = {1872-7077 1382-6689},
year = {2024},
date = {2024-04-01},
journal = {Environmental toxicology and pharmacology},
volume = {107},
pages = {104424},
abstract = {The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFβ1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.},
note = {Place: Netherlands},
keywords = {*Benzo(a)pyrene/toxicity, *Epithelial Cells/metabolism, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Benzo[a]pyrene, DNA Damage, Epithelial-Mesenchymal Transition, Human bronchial epithelial cells, Humans, Ligands, Receptors},
pubstate = {published},
tppubtype = {article}
}
The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFβ1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.
2021
Vondráček, Jan; Machala, Miroslav
The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action. Journal Article
In: Current drug metabolism, vol. 22, no. 8, pp. 584–595, 2021, ISSN: 1875-5453 1389-2002, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Activation, AhR, Animals, Benzo[a]pyrene, Cell Proliferation, Cell Survival, cell-to-cell communication, DNA Damage, Environmental Pollutants/*pharmacokinetics/*toxicity, Humans, Metabolic, Mutagens/*pharmacokinetics/*toxicity, oxidative stress, PAH metabolism., Polycyclic Aromatic Hydrocarbons/*pharmacokinetics/*toxicity
@article{vondracek_role_2021,
title = {The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action.},
author = {Jan Vondráček and Miroslav Machala},
doi = {10.2174/1389200221999201125205725},
issn = {1875-5453 1389-2002},
year = {2021},
date = {2021-01-01},
journal = {Current drug metabolism},
volume = {22},
number = {8},
pages = {584–595},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors, or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase and Ca(2+)-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations of the available data, it seems evident that more attention should be paid to the discrimination between the potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight into the mechanisms of toxicity of this large and diverse group of environmental pollutants.},
note = {Place: Netherlands},
keywords = {Activation, AhR, Animals, Benzo[a]pyrene, Cell Proliferation, Cell Survival, cell-to-cell communication, DNA Damage, Environmental Pollutants/*pharmacokinetics/*toxicity, Humans, Metabolic, Mutagens/*pharmacokinetics/*toxicity, oxidative stress, PAH metabolism., Polycyclic Aromatic Hydrocarbons/*pharmacokinetics/*toxicity},
pubstate = {published},
tppubtype = {article}
}
Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors, or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase and Ca(2+)-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations of the available data, it seems evident that more attention should be paid to the discrimination between the potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight into the mechanisms of toxicity of this large and diverse group of environmental pollutants.