Soybean isoflavones protect SH-SY5Y neurons from atrazine-induced toxicity by activating mitophagy through stimulation of the BEX2/BNIP3/NIX pathway

• Published in: Ecotoxicology and environmental safety 2021-12, Vol.227, p.112886, Article 112886
• Main Authors: Li, Peng, Yao, Li-Yan, Jiang, Yu-Jia, Wang, Dan-Dan, Wang, Ting, Wu, Yan-Ping, Li, Bai-Xiang, Li, Xue-Ting
• Format: Article
• Language: English
• Subjects: Atrazine; Atrazine - toxicity; Dopaminergic Neurons; Glycine max - chemistry; Humans; Isoflavones - pharmacology; Membrane Proteins; Mitophagy; Nerve Tissue Proteins; Neurotoxicity; Prevention; Proto-Oncogene Proteins; Soybean isoflavones; Tumor Suppressor Proteins
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2021.112886

Atrazine (ATR) is a widely used herbicide that can induce the degeneration of dopaminergic (DAergic) neurons in the substantia nigra, resulting in a Parkinson’s disease-like syndrome. Despite the high risk of environmental exposure, few studies have investigated strategies for the prevention of ATR neurotoxicity. Our previous studies demonstrated that ATR can impair mitochondrial function, leading to metabolic failure. Cells maintain mitochondrial quality through selective autophagic elimination, termed mitophagy. Soybean isoflavones (SI) possess multiple beneficial bioactivities, including preservation of mitochondria function, so it was hypothesized that SI can protect neurons against ATR toxicity by promoting mitophagy. Pretreatment of SH-SY5Y neurons with SI prevented ATR-induced metabolic failure and cytotoxicity as assessed by intracellular ATP, Na+-K+-ATPase activity, mitochondrial membrane potential, and cell viability assays. The neuroprotective efficacy of SI was superior to the major individual components genistein, daidzein, and glycitein. Ultrastructural analyses revealed that ATR induced mitochondrial damage, while SI promoted the sequestration of damaged mitochondria into autophagic vesicles. Soybean isoflavones also induced mitophagy as evidenced by upregulated expression of BNIP3/NIX, BEX2, and LC3-II, while co-treatment with the mitophagy inhibitor Mdivi-1 blocked SI-mediated neuroprotection and prevented SI from reversing ATR-induced BEX2 downregulation. Furthermore, BEX2 knockdown inhibited SI-induced activation of the BNIP3/NIX pathway, mitophagy, and neuroprotection. These findings suggest that SI protects against ATR-induced mitochondrial dysfunction and neurotoxicity by activating the BEX2/BNIP3/NIX pathway. [Display omitted] •Soybean isoflavones protected against neurotoxicity of the herbicide atrazine.•Soybean isoflavones-mediated neuroprotection was dependent on mitophagy.•Soybean isoflavones-induced mitophagy was mediated by the BEX2/BNIP3/NIX pathway.•Soybean isoflavones may protect against ATR-induced neurotoxicity in exposed humans.