Recent studies suggest that N, N-diethyl-meta-toluamide (DEET) is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an ...insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 µg/mg), DEET was a poor acetylcholinesterase inhibitor (<10% inhibition), even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6-12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 µM), but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na(+) and K(+) channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM) sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans.
Emerging insecticide resistance is a major issue for vector control. It decreases the effectiveness of insecticides, thereby requiring greater quantities for comparable control with a net increase in ...risk of disease resurgence, product cost, and damage risk to the ecosystem. Pyrethroid resistance has been documented in Puerto Rican populations of Aedes aegypti (L.) mosquitoes. In this study, topical toxicity of five insecticides (permethrin, etofenprox, deltamethrin, DDT, transfluthrin) was determined for susceptible (Orlando-ORL) and resistant (Puerto Rico-PR) strains of Ae. aegypti. Resistance ratios were calculated using LD50 values, and high resistance ratios for permethrin (112) and etofenprox (228) were observed for the Puerto Rico strain. Behavioral differences in blood-feeding activity for pyrethroid-resistant and pyrethroid-susceptible strains of Ae. aegypti when exposed to pyrethroid-treated cloth were also explored. Strains were exposed for 15 min to a range of concentrations of pyrethroid-treated uniform fabric in a cage that contained 60 female Ae. aegypti mosquitoes. Interestingly, the resistance ratios for blood-feeding were similar for permethrin (61) and etofenprox (70), but were lower than their respective resistance ratios for topical toxicity, suggesting that knockdown resistance was the primary mechanism of resistance in the blood feeding assays. Results showed a rightward shift in the dose-response curves for blood-feeding that indicated higher concentrations of pyrethroids were necessary to deter blood-feeding behavior in the pyrethroid-resistant Puerto Rican strain of Ae. aegypti.
The combined effect of global warming and insecticide exposure on the spread of mosquito-borne diseases is poorly studied. In our opinion, more resources should be diverted to this topic to further ...research efforts and deal with this increasing threat. It is particularly important to determine how Aedes, Anopheles, and Culex vector species cope with insecticide exposure under warming temperatures, as well as how both stressors may impact the activity of mosquito biocontrol agents. Herein, we promote a discussion on the topic, fostering a research agenda with insights for the longer-term implementation of mosquito control strategies under the Integrated Vector Management framework.
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•Limited information is available on the joint effect of global warming and insecticide exposure on mosquito vectors.•The impact of insecticide exposure under warming temperatures has been mainly studied on Culex pipiens.•A severe lack of information about Aedes and Anopheles species outlines the need of further research efforts.•Both stressors may have a detrimental impact on mosquito biocontrol agents, particularly on predatory behavior.•We discuss major research challenges for long-term implementation of mosquito control within the IVM.
Is DEET a dangerous neurotoxicant? Swale, Daniel R; Bloomquist, Jeffrey R
Pest management science,
August 2019, Letnik:
75, Številka:
8
Journal Article
Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets ...only employ pyrethroids, insecticides that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess low mammalian toxicity. In this review, we will describe efforts to develop highly species-specific and resistance-breaking inhibitors of An. gambiae acetylcholinesterase (AgAChE). These efforts have been greatly aided by advances in knowledge of the structure of the enzyme, and two major inhibitor design strategies have been explored. Since AgAChE possesses an unpaired Cys residue not present in mammalian AChE, a logical strategy to achieve selective inhibition involves design of compounds that could ligate that Cys. A second strategy involves the design of new molecules to target the catalytic serine of the enzyme. Here the challenge is not only to achieve high inhibition selectivity vs human AChE, but also to demonstrate toxicity to An. gambiae that carry the G119S resistance mutation of AgAChE. The advances made and challenges remaining will be presented. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity".
Phytochemicals have been considered as alternatives for conventional pesticides because of their low mammalian toxicity and environmental safety. They usually display less potent insecticidal effects ...than synthetic compounds, but may express as yet unknown modes of action. In the current study, we evaluated 14 plant essential oils for their toxicities and synergistic effects with carbaryl and permethrin against fourth instars of Aedes aegypti (L.) as well as 5-7-d-old adults. Six essential oils showed significant synergistic effects with carbaryl at 10–50 mg/liter, but paradoxically all of them decreased the toxicity of permethrin against Ae. aegypti larvae. None showed toxicity or synergistic effects on Ae. aegypti adults, at doses up to 2,000 ng/insect. The six essential oils displaying synergistic effects in Ae. aegypti larvae inhibited the in vitro activities of cytochrome P450 monooxygenases and carboxylesterases in the low milligram per liter range. The data indicated that cytochrome P450 monooxygenases and carboxylesterase were probably targets for these natural synergists. Thus, the mechanism of synergism was most likely inhibition of metabolism and not interacting target site effects.
Because of the increased interest in plant essential oils (PEO) for both home pest control and personal bite protection, the ability of fir needle (Abies balsamea) oil to synergize the 1-h knockdown ...and 24-h toxicity of 9 different synthetic insecticides was evaluated. Fir needle oil strongly synergized knockdown of the neonicotinoids, clothianidin, and thiamethoxam (between 16- and 24-fold), as well as natural pyrethrins (12-fold), but had less effect with organophosphates and fipronil. For 24-h mortality, only pirimiphos-methyl was strongly synergized by fir needle oil pretreatment (18-fold). Chemical analysis and testing identified delta-3-carene is the most bioactive constituent, producing synergism similar to that of the whole oil. In fact, this constituent synergized the 24-h mortality of clothianidin to a higher degree than fir needle oil itself (4.9-fold vs. 2.4-fold). Synergism is unlikely to be mediated by effects on the nervous system, as fir needle oil caused no change in mosquito central nervous system firing at 100 ppm and did not synergize an inactive concentration of natural pyrethrins (10 nM).To better understand fir needle oil effects, we evaluated the ability of pretreatment with this oil to impact Aedes aegypti monooxygenase degradation of a model substrate, 7-ethoxycoumarin. Interestingly, both fir needle oil and delta-3-carene caused a significant increase in metabolic degradation of 7-ethoxycoumarin, perhaps indicating they upregulate oxidative metabolic processes. Such an action would explain why fir needle oil enhances knockdown, but not 24-h mortality for most of the insecticides studied here, whereas increased bioactivation would explain the synergism of pirimiphos-methyl toxicity.
Previous studies have shown that blockers of voltage-gated potassium (Kv) channels, such as 4-aminopyridine (4-AP) and 2-methoxy-N-((1-phenylcyclopentyl)methyl)benzamide (2-MPB) synergized pyrethroid ...toxicity as well, or better than, piperonyl butoxide. The present study assessed the involvement of different Kv channels as possible pyrethroid synergist targets in Drosophila melanogaster. Three Kv1 mutants (Sh5, Sh133, and ShM) and one Kv2 mutant (Shab3) were tested. All Kv1 mutant flies showed increased sensitivity to permethrin in topical and glass contact toxicity assays, of 2- to 11-fold. Central nervous system (CNS) recordings of larval D. melanogaster showed a similar pattern of increased sensitivity. Potentiated effects were also observed with deltamethrin on the mutants Sh5 (30- to 35-fold) and Sh133 (33- to 47-fold), but the mutant ShM showed little change in sensitivity. In contrast, the Shab3 strain showed toxicity and physiological effects of both pyrethroids that were similar to the susceptible OR strain. Thus, some K+ channel mutations mimicked the synergistic effect of channel blockers. Additional studies showed that Shab3 had the highest sensitivity to 4-AP in topical assays, and the Shaker-null mutants, ShM and Sh133 showed greater sensitivity to 2-MPB in CNS recordings of larval D. melanogaster. These results suggest that Kv1 channels are a useful synergist target for pyrethroids, as assessed both in whole insects and at the level of the nervous system. Thus, Kv1-targeting compounds can potentially serve as insect control tools to reduce pyrethroid use via synergistic action.
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•Kv1 mutant flies showed increased toxicity to permethrin.•Neuronal activity of mutants had a similar pattern of increased sensitivity.•The ShM and Shab3 mutants had less effect on permethrin activity.•Some K+ channel mutations mimicked the synergistic effect of channel blockers.•K+ channel blockers can be effective synergists of pyrethroids.
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