title: Molecular mechanisms of discrotophos-induced toxicity in HepG2 cells: The role of CSA in oxidative stress.
abstract: Dicrotophos (Dic), an insecticide and acaricide, is used against a variety of sucking, boring and chewing pests. It was proven that Dic induced oxidative DNA damage in HepG2 cells. However, the molecular mechanisms of this compound were still unclear. First of all, the cytotoxicity and oxidative DNA damage were confirmed. Next, using RNA-seq for detecting differential expressed genes (DEGs) in cells treated with 50 μM Dic for 24 h, we showed that the dysregulation of these genes, irrespective of up (1298 genes) or down (2125 genes) regulation, could be attributed to some diverse pathways/metabolisms using KEGG analysis, particularly in DNA damage responses (DDRs) such as oxidative phosphorylation, nucleotide excision repair and cell cycle arrest. Validation of some randomly selected DDR genes confirmed RNA-seq results. We further demonstrated that Dic induced ROS overproduction, the loss of mitochondrial depolarization and cell cycle arrest in the G0/G1 phase. In addition, we also definitely clarified the role of CSA, a nucleotide excision repair enzymes in Dic-treated cells. Collectively, our results showed that various mechanisms of Dic-induced toxicity in HepG2 cells including downregulation of some genes related to nucleotide excision repair including CSA and increased oxidative stress.
authors.affiliation: Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.
authors.forename: You-Cheng
authors.initials: YC
authors.lastname: Hseu
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Tung-Wei
authors.initials: TW
authors.lastname: Hsu
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Heng-Dao
authors.initials: HD
authors.lastname: Lin
authors.affiliation: Department of Medical Technology, Yuanpei Institute of Science and Technology, Hsin-Chu, Taiwan.
authors.forename: Chin Hui
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan. Electronic address: osycchna@ksts.seed.net.tw.
authors.forename: Ssu Ching
authors.initials: SC
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C095472:ERCC8 protein, human; D009943:Organophosphorus Compounds; D014157:Transcription Factors; C000944:dicrotophos; D045643:DNA Repair Enzymes
keywords: Apoptosis; Autophagy; CSA; Dicrotophos; RNA-seq; ROS