Low doses of the organic insecticide spinosad trigger lysosomal defects, elevated ROS, lipid dysregulation, and neurodegeneration in flies.
Low doses of the organic insecticide spinosad trigger lysosomal defects, elevated ROS, lipid dysregulation, and neurodegeneration in flies.
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DOI：
10.7554/elife.73812
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发表时间：
2022-02-22
期刊：
影响因子：
7.7
通讯作者：
Bellen HJ
中科院分区：
文献类型：
--
作者：
Martelli F;Hernandes NH;Zuo Z;Wang J;Wong CO;Karagas NE;Roessner U;Rupasinghe T;Robin C;Venkatachalam K;Perry T;Batterham P;Bellen HJ
大规模使用杀虫剂是控制农业害虫的首要武器。然而，越来越多的证据表明，这是导致许多有益昆虫物种的全球种群数量减少的原因。多杀菌素作为合成杀虫剂的有机替代品出现，被认为对有益昆虫的危害较小，但其作用模式尚不清楚。在果蝇身上，我们证明了低剂量的多杀菌素拮抗其神经靶-烟碱型乙酰胆碱受体亚单位α6(nAChRα6)，从而降低胆碱能反应。我们发现，nAChRα6受体被转运到溶酶体，在低剂量的多杀菌素治疗下，溶酶体变大和数量增加。溶酶体功能障碍与线粒体应激和中枢神经系统中活性氧簇(ROS)水平升高有关，中枢神经系统广泛表达nAChRα6。ROS以nAChRα6依赖的方式干扰代谢组织中的脂质储存。抗氧化剂N-乙酰半胱氨酸酰胺可改善多杀菌素的毒性。成年处女长期接触低剂量的多杀菌素会导致线粒体缺陷、严重的神经变性和失明。低剂量暴露的这些有害影响需要严格调查其对有益昆虫的影响。
Large-scale insecticide application is a primary weapon in the control of insect pests in agriculture. However, a growing body of evidence indicates that it is contributing to the global decline in population sizes of many beneficial insect species. Spinosad emerged as an organic alternative to synthetic insecticides and is considered less harmful to beneficial insects, yet its mode of action remains unclear. Using Drosophila, we show that low doses of spinosad antagonize its neuronal target, the nicotinic acetylcholine receptor subunit alpha 6 (nAChRα6), reducing the cholinergic response. We show that the nAChRα6 receptors are transported to lysosomes that become enlarged and increase in number upon low doses of spinosad treatment. Lysosomal dysfunction is associated with mitochondrial stress and elevated levels of reactive oxygen species (ROS) in the central nervous system where nAChRα6 is broadly expressed. ROS disturb lipid storage in metabolic tissues in an nAChRα6-dependent manner. Spinosad toxicity is ameliorated with the antioxidant N-acetylcysteine amide. Chronic exposure of adult virgin females to low doses of spinosad leads to mitochondrial defects, severe neurodegeneration, and blindness. These deleterious effects of low-dose exposures warrant rigorous investigation of its impacts on beneficial insects.