Abstract
Fungicides often cause genotoxic stress and neurodevelopmental disorders such as autism (ASD). Fungicide-azoxystrobin (AZOX) showed acute and chronic toxicity to various organisms, and remained a concern for ill effects in developing neurons. We evaluated the neurotoxicity of AZOX in developing mouse brains, and observed prenatal exposure to AZOX reduced neuronal viability, neurite outgrowth, and cortical migration process in developing brains. The 50% inhibitory concentration (IC50) of AZOX for acute (24 h) and chronic (7 days) exposures were 30 and 10 μM, respectively. Loss in viability was due to the accumulation of reactive oxygen species (ROS), and inhibited neurite outgrowth was due to the deactivation of mTORC1 kinase activity. Pretreatment with ROS scavenger- N-acetylcysteine (NAC) reserved the viability loss and forced activation of mTORC1 kinase revived the neurite outgrowth in AZOX treated neurons. Intra-amniotic injection of AZOX coupled with in utero electroporation of GFP-labelled plasmid in E15.5 mouse was performed and 20 mg/kg AZOX inhibited radial neuronal migration. Moreover, the accumulation of mitochondria was significantly reduced in AZOX treated primary neurons, indicative of mitochondrial deactivation and induction of apoptosis, which was quantified by Bcl2/Bax ratio and caspase 3 cleavage assay. This study elucidated the neurotoxicity of AZOX and explained the possible cure from it.
Highlights
Azoxystrobin (AZOX) is a common strobilurins group fungicide widely used in agriculture to protect crops from fungal diseases [1]
We examined the ill-effect of AZOX in neuronal maturation and development in vitro and in vivo mouse models
AZOX was exposed to primary cortical neuronal cultures for a short interval and a long interval
Summary
Azoxystrobin (AZOX) is a common strobilurins group fungicide widely used in agriculture to protect crops from fungal diseases [1]. The imbalance in energy production and mitochondrial health could be fatal for the neurons [4] This can either induce premature cell death or cell senescence, as a consequence, the neurodevelopment process could be hampered [5]. A previous study indicates that AZOX exposure altered lipid and glucose metabolism in liver cells [12], and affected the AMP-activated protein kinase (AMPK) pathway. It induces mitochondria-mediated apoptosis in KYSE-150esophageal squamous carcinoma cells [2]. We observed the cortical brain development was impaired in AZOX treated groups due to inhibited neuronal migration and primary neurite formation process. Either forced activation of mTORC1 or N-acetylcysteine (NAC) treatment ameliorated neurite defects and cell viability loss in primary cortical neurons caused by AZOX
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