Mechanistic Interplay Between Autophagy and Apoptotic Signaling in Endosulfan-Induced Dopaminergic Neurotoxicity: Relevance to the Adverse Outcome Pathway in Pesticide Neurotoxicity

Toxicological Sciences : an Official Journal of the Society of Toxicology
Chunjuan SongAnumantha G Kanthasamy

Abstract

Chronic exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). Previously, we showed that dieldrin induces dopaminergic neurotoxicity by activating a cascade of apoptotic signaling pathways in experimental models of PD. Here, we systematically investigated endosulfan's effect on the interplay between apoptosis and autophagy in dopaminergic neuronal cell models of PD. Exposing N27 dopaminergic neuronal cells to endosulfan rapidly induced autophagy, indicated by an increased number of autophagosomes and LC3-II accumulation. Prolonged endosulfan exposure (>9 h) triggered apoptotic signaling, including caspase-2 and -3 activation and protein kinase C delta (PKCδ) proteolytic activation, ultimately leading to cell death, thus demonstrating that autophagy precedes apoptosis during endosulfan neurotoxicity. Furthermore, inhibiting autophagy with wortmannin, a phosphoinositide 3-kinase inhibitor, potentiated endosulfan-induced apoptosis, suggesting that autophagy is an early protective response against endosulfan. Additionally, Beclin-1, a major regulator of autophagy, was cleaved during the initiation of apoptotic cell death, and the cleavage was predominantly mediated by caspase-2. Also, caspase-2 a...Continue Reading

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Citations

Nov 28, 2019·Cellular and Molecular Neurobiology·Fatemeh SafariFarzaneh Khademi
Mar 18, 2019·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Jie LuoAnumantha G Kanthasamy
Oct 22, 2020·International Journal of Molecular Sciences·Richard L JayarajFakhreya Yousuf Jalal
Feb 6, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Dahlia TriningsihYoun Ju Lee
Jul 22, 2021·Archives of Pharmacal Research·Eun-Joo ShinHyoung-Chun Kim
Jul 28, 2021·Journal of Biomedical Materials Research. Part B, Applied Biomaterials·Benjamin W SchlichtmannBalaji Narasimhan

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