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

0556112 - BFÚ 2023 RIV NL eng J - Journal Article
Šimečková, P. - Pěnčíková, K. - Kováč, O. - Slavík, J. - Parenicova, M. - Vondráček, Jan - Machala, M.
In vitro profiling of toxic effects of environmental polycyclic aromatic hydrocarbons on nuclear receptor signaling, disruption of endogenous metabolism and induction of cellular stress.
Science of the Total Environment. Roč. 815, APR 1 2022 (2022), č. článku 151967. ISSN 0048-9697. E-ISSN 1879-1026
R&D Projects: GA ČR(CZ) GA21-00533S
Institutional support: RVO:68081707
Keywords : pregnane-x-receptor * primary human hepatocytes * aryl-hydrocarbon * estrogen-receptor * mediated activity * hepg2 cells * cross-talk * activation
OECD category: Ecology
Impact factor: 9.8, year: 2022
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/pii/S0048969721070431?via%3Dihub

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 stress markers, 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 alpha (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 alpha 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 alpha (in case of the AhR-activating PAHsChry, 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 mechanism underlying their impact on nuclear receptor signaling, endogenous metabolism and induction of early stress and genotoxicity markers.
Permanent Link: https://hdl.handle.net/11104/0339759