Introduction
Insecticide applications maximize crop yield, but negatively impact populations of insects that provide beneficial services in agriculture and horticulture (Sánchez-Bayo and Wyckhuys, 2019). The global decline in population sizes of these beneficial insects creates challenges for ecosystems and farming. Although estimates differ depending on the regions and the methodologies used (Wagner et al., 2021), one recent study suggests an approximately 9% decline in terrestrial insect abundance per decade since 1925 (van Klink et al., 2020). While the precise extent to which insecticides are involved remains undetermined, they have consistently been associated as a key factor, along with climate change, habitat loss, and increased levels of pathogens and parasites (Cardoso et al., 2020; Sánchez-Bayo and Wyckhuys, 2019; Wagner et al., 2021). Much attention has been given to neonicotinoid insecticides, both in the scientific literature and in public discourse, because of the evidence that these chemicals contribute to the bee colony collapse phenomenon (Lu et al., 2014; Lundin et al., 2015).
In assessing the risk posed by insecticides, it is important to study the molecular and cellular events that unfold following the interaction between the insecticide and its target. Many insecticides target ion channels in the nervous system. At the high doses used to kill pests, these insecticides produce massive perturbations to the flux of ions in neurons, resulting in lethality (Breer and Sattelle, 1987; Perry and Batterham, 2018; Scott and Buchon, 2019). But non-pest insects are likely to be exposed to much lower doses, and the downstream physiological processes that are triggered are poorly understood. In a recent study, low doses of the neonicotinoid imidacloprid were shown to stimulate an enduring flux of calcium into neurons via the targeted ligand-gated 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. Mitochondrial stress leads to a significant drop in energy levels, neurodegeneration, and blindness (Martelli et al., 2020). Evidence of compromised immune function was also presented, supporting other studies (Chmiel et al., 2019). Many other synthetic insecticides are known to elevate the levels of ROS (Karami-Mohajeri and Abdollahi, 2011; Lukaszewicz-Hussain, 2010; Wang et al., 2016) and may precipitate similar downstream impacts. Given current concerns about synthetic insecticides, a detailed analysis of the molecular and cellular impacts of organic alternatives is warranted. Here, we report such an analysis for an insecticide of the spinosyn class, spinosad.
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Spinosad is an 85%:15% mixture of spinosyns A and D, natural fermentation products of the soil bacterium Saccharopolyspora spinosa. It occupies a small (3%) but growing share of the global insecticide market (Sparks et al., 2017). It is registered for use in more than 80 countries and applied to over 200 crops to control numerous pest insects (Biondi et al., 2012). Recommended dose rates vary greatly depending on the pest and crop, ranging from 96 parts per million (ppm) for Brassica crops to 480 ppm in apple fields (Biondi et al., 2012). Like other insecticides, the level of spinosad residues found in the field varies greatly depending on the formulation, the application mode and dose used, environmental conditions, and proximity to the site of application. If protected from light, spinosad shows a half-life of up to 200 days (Cleveland et al., 2002).
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Spinosad is a hydrophobic compound belonging to a lipid class known as polyketide macrolactones. Studies using mutants, field-derived-resistant strains, and heterologous expression have shown that spinosad targets the highly conserved nAChRα6 subunit of nAChRs in Drosophila melanogaster (hereafter Dα6) and a range of other insect species (Perry et al., 2015; Perry et al., 2007). Spinosad is an allosteric modulator, binding to a site in the C terminal region of the protein (Puinean et al., 2013; Somers et al., 2015). Salgado and Saar, 2004 found that spinosad allosterically activates non-desensitized nAChRs, but that low doses were also capable of antagonizing the desensitized nAChRs. It is currently accepted that spinosad causes an increased sensitivity to ACh in certain nAChRs and an enhanced response at some GABAergic synapses, causing involuntary muscle contractions, paralysis, and death (Biondi et al., 2012; Salgado, 1998). However, a recent study (Nguyen et al., 2021) showed that both acute and chronic exposures to spinosad cause Dα6 protein levels in the larval brain to decrease. A rapid loss of Dα6 protein during acute exposure was blocked by inhibiting the proteasome system (Nguyen et al., 2021). As Dα6 loss-of-function mutants are both highly resistant to spinosad and viable (Perry et al., 2021; Perry et al., 2007), it was suggested that the toxicity of spinosad may be due to the overloading of protein degradation pathways and/or the internalization of spinosad where it may cause cellular damage. Higher doses of spinosad than the ones used here have been shown to cause cellular damage via mitochondrial dysfunction, oxidative stress, and programmed cell death in cultured insect cells (Spodoptera frugiperda Sf9) (Xu et al., 2017; Yang et al., 2017).
Here, we show that spinosad by itself does not increase Ca2+ flux in Drosophila neurons. Indeed, the response elicited by a cholinergic agonist is stunted upon spinosad treatment. Following exposure to spinosad, Dα6 cholinergic receptors are endocytosed and trafficked to the lysosomes, leading to lysosomal dysfunction. This dysfunction is associated with high levels of oxidative stress. Antioxidant treatment prevents the accumulation of ROS, but not lysosomal expansion. ROS is a key factor in the mode of action of spinosad at low doses, triggering a cascade of damage that results in mitochondrial stress and reduced energy levels. Low chronic exposures lead to extensive neurodegeneration in the central brain and blindness. Flies carrying a Dα6 loss-of-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-pest insects at low doses.
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