Neurotoxicity of a pyrethroid pesticide deltamethrin is associated with the imbalance in proteolytic systems caused by mitophagy activation and proteasome inhibition

• Published in: Toxicology and applied pharmacology 2021-11, Vol.430, p.115723, Article 115723
• Main Authors: Hirano, Tetsushi, Suzuki, Nihei, Ikenaka, Yoshinori, Hoshi, Nobuhiko, Tabuchi, Yoshiaki
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Autophagy; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Deltamethrin; Endoplasmic Reticulum Stress - drug effects; Gene Expression Regulation; Insecticides - toxicity; Mice; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - pathology; Mitochondrial dysfunction; Mitophagy - drug effects; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Neurotoxicity; Neurotoxicity Syndromes - enzymology; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - genetics; Neurotoxicity Syndromes - pathology; Nitriles - toxicity; Oxidative Stress - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - toxicity; Proteolysis; Pyrethrins - toxicity; Pyrethroid; Transcriptome; Ubiquitin-proteasome system
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2021.115723

Pyrethroids are one of the most commonly used classes of synthetic pesticides in the world. Recent laboratory and epidemiological evidence suggested that pyrethroids have potential adverse effects in the mammalian brain; however, the underlying mechanisms of the neurotoxic effects of pyrethroids have not been fully elucidated. In the present study, we investigated the mechanisms of effects of a type II pyrethroid deltamethrin (DM) in a neuronal cell model focusing on the proteolytic function, including autophagy and the ubiquitin-proteasome system. We confirmed that a micromolar concentration of DM dose-dependently decreased the cell viability and induced apoptotic cell death. Our results showed that DM enhanced autophagy in association with an accumulation of autophagosomes and increase in the levels of autophagy markers LC3-II/LC3-I ratio and p62 which were much elevated in the presence of lysosomal inhibitors bafilomycin A1 and chloroquine. We also found that DM caused a dysfunction of mitochondria with a decrease of mitochondrial membrane potential and mitochondrial DNA copy number as well as colocalization with autophagosomes. Moreover, a decrease in the activities of three major proteasomal enzymes and an accumulation of ubiquitinated proteins were observed by the exposure to DM. Transcriptome analysis revealed that up-regulated genes supported the activation of autophagy with induction of cellular stress responses including oxidative stress and endoplasmic reticulum stress, while down-regulated genes related to the cell cycle and DNA replication. These findings provide novel insights into the neurotoxicity of DM which underlie the imbalance in proteolytic function caused by mitophagy activation and proteasome inhibition. [Display omitted] •Pyrethroid pesticide deltamethrin (DM) had neurotoxicity on mouse neuron model.•DM induced mitophagy activation along with proteasome inhibition.•DM up-regulated genes associated with autophagy and cellular stress responses.•DM down-regulated genes related to cell cycle and DNA replication.•Imbalance in proteolytic systems contributed to the neurotoxicity of pyrethroids.