In vitro profiling of toxic effects of environmental polycyclic aromatic hydrocarbons on nuclear receptor signaling, disruption of endogenous metabolism and induction of cellular stress

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F22%3AN0000094" target="_blank" >RIV/00027162:_____/22:N0000094 - isvavai.cz</a>

Výsledek na webu

<a href="https://biodetectionsystems.com/news/13th-biodetectors-conference-2022/" target="_blank" >https://biodetectionsystems.com/news/13th-biodetectors-conference-2022/</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

In vitro profiling of toxic effects of environmental polycyclic aromatic hydrocarbons on nuclear receptor signaling, disruption of endogenous metabolism and induction of cellular stress

Popis výsledku v původním jazyce

Polycyclic aromatic hydrocarbons (PAHs) can interact with multiple intracellular receptors and related signaling pathways. Here, we comprehensively evaluated the toxicity profiles of six environmentally relevant PAHs differing in structure, genotoxicity and their ability to activate the aryl hydrocarbon receptor (AhR). We focused particularly on their impact on intracellular hormone-, xenobiotic- and lipid-sensing receptors, as well as on cellular stress markers, combining a battery of human reporter gene assays (in various human cell models) and RT-qPCR evaluation of endogenous gene expression in human hepatocyte-like HepaRG cells. Low-molecular-weight PAHs, with low AhR affinity, activated or potentiated the activation of ERalpha, TRalpha and CAR receptors. In contrast, exposure to the AhR-activating PAHs was linked with suppression of ERalpha, AR, PXR and PPARalpha activities. PAHs with AhR activity also deregulated glucose and lipid metabolism, and induced several early stress and DNA damage response markers [1]. The observed cross-talk of PAH-activated AhR with a series of nuclear receptors confirmed that the AhR-mediated activity represents one of key events in toxicity of PAHs. Recently, we estimated the AhR-mediated activities of a large set of environmental PAHs in human gene reporter AZ-AhR cell line, with an aim to develop the human AhR based REP values, with potential implications for risk assessment of PAHs. The order for REPs of individual PAHs in human cells largely corresponded with the available data from rodent-based experimental CALUX assays; nevertheless, we also identified differences up to one order of magnitude in REP values of PAHs between human and rodent cells. Higher REP values were found in human cells e.g. for some important environmental PAHs, such as indeno[1,2,3-cd]pyrene, benz[a]anthracene or benzo[b]fluoranthene, while lower REP values were determined for methylated PAHs [2]. Interestingly, also, when we investigated the AhR-mediated activities of six ring PAHs (with molecular weight 302) in the human AZ-AhR cell model, we observed that they possess significant AhR potencies and may contribute significantly to the AhR activity of complex environmental mixtures [3]. At present, the mechanism underlying the crosstalk of human AhR with NRs (other than ERalpha) remain poorly defined. The mechanisms underlying interactions of both PAHs and their metabolites with the networks of AhR and other NRs thus deserve more attention, as they could be involved in the toxic action of these important environmental pollutants.

Název v anglickém jazyce

In vitro profiling of toxic effects of environmental polycyclic aromatic hydrocarbons on nuclear receptor signaling, disruption of endogenous metabolism and induction of cellular stress

Popis výsledku anglicky

Polycyclic aromatic hydrocarbons (PAHs) can interact with multiple intracellular receptors and related signaling pathways. Here, we comprehensively evaluated the toxicity profiles of six environmentally relevant PAHs differing in structure, genotoxicity and their ability to activate the aryl hydrocarbon receptor (AhR). We focused particularly on their impact on intracellular hormone-, xenobiotic- and lipid-sensing receptors, as well as on cellular stress markers, combining a battery of human reporter gene assays (in various human cell models) and RT-qPCR evaluation of endogenous gene expression in human hepatocyte-like HepaRG cells. Low-molecular-weight PAHs, with low AhR affinity, activated or potentiated the activation of ERalpha, TRalpha and CAR receptors. In contrast, exposure to the AhR-activating PAHs was linked with suppression of ERalpha, AR, PXR and PPARalpha activities. PAHs with AhR activity also deregulated glucose and lipid metabolism, and induced several early stress and DNA damage response markers [1]. The observed cross-talk of PAH-activated AhR with a series of nuclear receptors confirmed that the AhR-mediated activity represents one of key events in toxicity of PAHs. Recently, we estimated the AhR-mediated activities of a large set of environmental PAHs in human gene reporter AZ-AhR cell line, with an aim to develop the human AhR based REP values, with potential implications for risk assessment of PAHs. The order for REPs of individual PAHs in human cells largely corresponded with the available data from rodent-based experimental CALUX assays; nevertheless, we also identified differences up to one order of magnitude in REP values of PAHs between human and rodent cells. Higher REP values were found in human cells e.g. for some important environmental PAHs, such as indeno[1,2,3-cd]pyrene, benz[a]anthracene or benzo[b]fluoranthene, while lower REP values were determined for methylated PAHs [2]. Interestingly, also, when we investigated the AhR-mediated activities of six ring PAHs (with molecular weight 302) in the human AZ-AhR cell model, we observed that they possess significant AhR potencies and may contribute significantly to the AhR activity of complex environmental mixtures [3]. At present, the mechanism underlying the crosstalk of human AhR with NRs (other than ERalpha) remain poorly defined. The mechanisms underlying interactions of both PAHs and their metabolites with the networks of AhR and other NRs thus deserve more attention, as they could be involved in the toxic action of these important environmental pollutants.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA21-00533S" target="_blank" >GA21-00533S: Nekonvenční environmentální ligandy Ah receptoru a jejich komplexní účinky in vitro</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů