Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes.
Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity. Interestingly, DLM treatment resulted in a caspase-independent but non-apoptotic cell death. Pre-treatment with pan-caspase inhibitor (ZVAD-FMK) could not rescue hepatocytes. Unaltered caspase-3 activity and absence of cleaved caspase-3 also corroborated our findings. Further, LDH release and Transmission electron microscopy (TEM) analysis demonstrated that DLM incites membrane disintegrity and necrotic damage. Immunochemical staining revealed an increased expression of inflammatory markers (TNFα, NFκB, iNOS, COX-2) following DLM treatment. Moreover, the enhanced RIPK3 expression in DLM treated groups and prominent rescue from cell death by GSK-872 indicated that DLM exposure could induce programmed necrosis in hepatocytes. The present study demonstrates that DLM could induce hepatotoxicity via non-apoptotic mode of cell death.
Environmental Carcinogenesis & Proteomics Laboratory, Food, Drug & Chemical Toxicology Group, Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow 226026, Uttar Pradesh, India.
Deepika
D
Arora
Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow 226026, Uttar Pradesh, India.
Mohammed Haris
MH
Siddiqui
Environmental Carcinogenesis & Proteomics Laboratory, Food, Drug & Chemical Toxicology Group, Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India. Electronic address: pradeep.sharma@iitr.res.in.
Pradeep Kumar
PK
Sharma
Environmental Carcinogenesis & Proteomics Laboratory, Food, Drug & Chemical Toxicology Group, Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India. Electronic address: yshukla@iitr.res.in.
Yogeshwer
Y
Shukla
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007306:Insecticides / Q000494:pharmacology; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D061251:Primary Cell Culture; D011722:Pyrethrins / Q000494:pharmacology*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007306:Insecticides; D016328:NF-kappa B; D009570:Nitriles; D011722:Pyrethrins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C017180:decamethrin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053148:Caspase 3
Caspase-independent; Deltamethrin; Hepatotoxicity; Primary hepatocytes; Programmed necrosis