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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F22%3AN0000013" target="_blank" >RIV/00027162:_____/22:N0000013 - isvavai.cz</a>

Alternative codes found

RIV/68081707:_____/22:00556112

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0048969721070431?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0048969721070431?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.scitotenv.2021.151967" target="_blank" >10.1016/j.scitotenv.2021.151967</a>

Result language

angličtina

Original language name

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

Original language description

Polycyclic aromatic hydrocarbons (PAHs) may interact with multiple intracellular receptors and related signaling pathways. 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 stressmarkers, combining a battery of human reporter gene assays and qRT-PCR evaluation of endogenous gene expression in human hepatocyte-like HepaRG cells, with LC/MS-MS analysis of cellular sphingolipids. The effects of PAHs included: activation of estrogen receptor α (in case of fluoranthene (Fla), pyrene (Pyr), benz[a]anthracene (BaA), benzo[a]pyrene (BaP)), suppression of androgen receptor activity (Fla, BaA, BaP and benzo[k]fluoranthene (BkF)), enhancement of dexamethasone-induced glucocorticoid receptor activity (chrysene (Chry), BaA, and BaP), and potentiation of triiodothyronine-induced thyroid receptor α activity (all tested PAHs). PAHs also induced transcription of endogenous gene targets of constitutive androstane receptor (Fla, Pyr), or repression of target genes of pregnane X receptor and peroxisome proliferator-activated receptor α (in case of the AhR-activating PAHs - Chry, BaA, BaP, and BkF) in HepaRG cells. In the same cell model, the AhR agonists reduced the expression of glucose metabolism genes (PCK1, G6PC and PDK4), and they up-regulated levels of glucosylceramides, together with a concomitant induction of expression of UGCG, glucosylceramide synthesis enzyme. Finally, both BaP and BkF were found to induce expression of early stress and genotoxicity markers: ATF3, EGR1, GDF15, CDKN1A/p21, and GADD45A mRNAs, while BaP alone increased levels of IL-6 mRNA. Overall, whereas low-molecular-weight PAHs exerted significant effects on nuclear receptors (with CYP2B6 induction observed already at nanomolar concentrations), the AhR activation by 4-ring and 5-ring PAHs appeared to be a key mechanismunderlying their impact on nuclear receptor signaling, endogenousmetabolism and induction of early stress and genotoxicity markers.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30108 - Toxicology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

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

Publication year

2022

Confidentiality

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

Name of the periodical

Science of The Total Environment

ISSN

0048-9697

e-ISSN

1879-1026

Volume of the periodical

815

Issue of the periodical within the volume

April 2022

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

14

Pages from-to

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UT code for WoS article

000766822200007

EID of the result in the Scopus database

2-s2.0-85120787323