Abstract
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.
Highlights
Insecticide applications maximize crop yield, but negatively impact populations of insects that provide beneficial services in agriculture and horticulture (Sánchez-B ayo and Wyckhuys, 2019)
As a starting point to study the systemic effects of low-dose spinosad exposure, a dose that would reduce the movement of third-instar larvae by 50% during a 2 hr exposure was determined
In contrast to imidacloprid, which leads to an enduring Ca2+ influx in neurons (Martelli et al, 2020), spinosad reduces the Ca2+ response mediated by Dα6
Summary
Insecticide applications maximize crop yield, but negatively impact populations of insects that provide beneficial services in agriculture and horticulture (Sánchez-B ayo and Wyckhuys, 2019). Low doses of the neonicotinoid imidacloprid were shown to stimulate an enduring flux of calcium into neurons via the targeted ligand-g ated ion channels (nicotinic acetylcholine receptors [nAChRs]) (Martelli et al, 2020). This causes an elevated level of reactive oxygen species (ROS) and oxidative damage that radiates from the brain to other tissues. Flies carrying a Dα6 loss-o f-function mutation show a mild increase in ROS, but no evidence of lysosomal dysfunction This indicates that the lysosomal defect observed in wild-type flies is not due to the absence of Dα6 from neuronal membranes but rather trafficking of Dα6 to lysosomes under conditions of spinosad exposure. Given the high degree of conservation of the spinosad target between insect species (Perry et al, 2015), our data indicate that this insecticide has the potential to cause harm in non-p est insects at low doses
Published Version
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