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N,N-dimethylformamide (DMF) is an organic compound widely used in industrial production processes as a solvent with a low evaporation rate. Excessive exposure to DMF may lead to liver damage. Oxidative stress has been reported as one of the main causes of DMF-induced hepatotoxicity. Several doses of DMF (0, 1, 5, and 10 mM) were used to treat HL-7702 cells for a relatively long period to simulate the actual exposure pattern in occupational settings, and oxidative stress was induced. Previous studies illustrated that circular RNA (circRNA) plays a vital role in sustaining hepatocyte physiological function. To explore whether aberrant circRNA expression is involved in DMF-induced excessive ROS generation and hepatotoxicity, high-throughput transcriptional sequencing was performed to identify the altered circRNA expression profiles in HL-7702 liver cells after treatment with 0, 75, or 150 mM DMF for 48 h. We found that levels of induced oxidative stress were similar to those in the long-term exposure model. Among the altered circRNAs, one circRNA (hsa_circ_0005915) was significantly upregulated after DMF exposure, and it affected DMF-mediated oxidative stress in HL-7702 cells. Further experiments revealed that hsa_circ_0005915 downregulated the expression of nuclear factor erythoid-2-related factor 2 (NRF2) at the post-transcriptional level via promoting the ubiquitination and degradation of NRF2, which led to the increase of ROS accumulation. Further investigation demonstrated that the expression levels of NRF2-regulated antioxidative genes-heme oxygenase 1 (HO1) and NAD(P)H quinone dehydrogenase 1 (NQO1)-indeed declined after the overexpression of hsa_circ_0005915. In vivo study also indicated that DMF exposure can upregulate the expression of mmu_circ_0007941 (homologous circRNA of hsa_circ_0005915) and downregulated Nrf2 and Ho1 proteins. In summary, our results revealed that hsa_circ_0005915 plays an important role in promoting DMF-induced oxidative stress by inhibiting the transcriptional activity of the NRF2/ARE axis, which provides a potential molecular mechanism of DMF-mediated hepatotoxicity.

Titel:	Hsa_circ_0005915 promotes N,N-dimethylformamide-induced oxidative stress in HL-7702 cells through NRF2/ARE axis.
Autor/in / Beteiligte Person:	Liu, Z ; He, Q ; Liu, Y ; Zhang, Y ; Cui, M ; Peng, H ; Wang, Y ; Chen, S ; Li, D ; Chen, L ; Xiao, Y ; Chen, W ; Wang, Q
Link:	Zum Volltext
Zeitschrift:	Toxicology, Jg. 458 (2021-06-30), S. 152838
Veröffentlichung:	Limerick : Elsevier ; <i>Original Publication</i>: Amsterdam. Elsevier/North-Holland., 2021
Medientyp:	academicJournal
ISSN:	1879-3185 (electronic)
DOI:	10.1016/j.tox.2021.152838
Schlagwort:	Chemical and Drug Induced Liver Injury genetics Chemical and Drug Induced Liver Injury metabolism Gene Expression Profiling Gene Expression Regulation drug effects Heme Oxygenase-1 metabolism Hepatocytes drug effects Hepatocytes metabolism Humans Membrane Potential, Mitochondrial drug effects MicroRNAs NAD(P)H Dehydrogenase (Quinone) metabolism Reactive Oxygen Species metabolism Signal Transduction drug effects Up-Regulation Dimethylformamide toxicity NF-E2-Related Factor 2 drug effects Oxidative Stress drug effects RNA, Circular genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Toxicology] 2021 Jun 30; Vol. 458, pp. 152838. <i>Date of Electronic Publication: </i>2021 Jun 19. MeSH Terms: Dimethylformamide / toxicity ; NF-E2-Related Factor 2 / drug effects ; Oxidative Stress / drug effects ; RNA, Circular / genetics ; Chemical and Drug Induced Liver Injury / genetics ; Chemical and Drug Induced Liver Injury / metabolism ; Gene Expression Profiling ; Gene Expression Regulation / drug effects ; Heme Oxygenase-1 / metabolism ; Hepatocytes / drug effects ; Hepatocytes / metabolism ; Humans ; Membrane Potential, Mitochondrial / drug effects ; MicroRNAs ; NAD(P)H Dehydrogenase (Quinone) / metabolism ; Reactive Oxygen Species / metabolism ; Signal Transduction / drug effects ; Up-Regulation Contributed Indexing: Keywords: Hepatotoxicity; Hsa_circ_0005915; N,N-dimethylformamide; NRF2/ARE; Reactive oxygen species Substance Nomenclature: 0 (MicroRNAs) ; 0 (NF-E2-Related Factor 2) ; 0 (NFE2L2 protein, human) ; 0 (RNA, Circular) ; 0 (Reactive Oxygen Species) ; 8696NH0Y2X (Dimethylformamide) ; EC 1.14.14.18 (HMOX1 protein, human) ; EC 1.14.14.18 (Heme Oxygenase-1) ; EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)) ; EC 1.6.5.2 (NQO1 protein, human) Entry Date(s): Date Created: 20210621 Date Completed: 20210805 Latest Revision: 20210805 Update Code: 20231215

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Hsa_circ_0005915 promotes N,N-dimethylformamide-induced oxidative stress in HL-7702 cells through NRF2/ARE axis.