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BACKGROUND: Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents. METHODS: We assessed 519 participants (11-17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl)benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, 17ß-estradiol, and testosterone was assessed using structural equation modeling. RESULTS: The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0-2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration (ß)=-0.19 95% confidence interval (CI): -0.31, -0.07], language [ß=-0.12 (95% CI: -0.23, -0.01)], and memory/learning [ß=-0.11 (95% CI: -0.22, 0.01)]. Glyphosate had a statistically significant negative association only with social perception [ß=-0.08 (95% CI: -0.14, -0.01)]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed. CONCLUSION: This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. https://doi.org/10.1289/EHP11383.

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Natural-based compounds with repellent activity arise nowadays with the possibility to replace commercial synthetic repellents wholly or partially, such as N,N-Diethyl-m-toluamide (DEET). It is due to DEET's demonstrated toxicity and cutaneous irritation for human beings. Besides, research recommends avoiding using it with kids and pregnant women. The search for a repellent product implies early stages of detailed research that resolve the modes of action against the target insect. Therefore the objective of the current study was to analyze neuronal electrophysiological signals and olfactory system protein expression when the Aedes aegypti mosquito with exposition to natural-based repellents. Adult females of Ae. aegypti of Rockefeller strain were exposed to specific concentrations of repellent compounds like geranyl acetate, α-bisabolol, nerolidol, and DEET. The neuronal effect was measured by electroantennography technique, and the effect of exposure to either DEET or a mixture of natural molecules on protein expression was determined with 2D-PAGE followed by MALDI-TOF-mass spectrometry (MS). This approach revealed that DEET affected proteins related to synapses and ATP production, whereas natural-based repellents increased transport, signaling, and detoxification proteins. The proteomic and electrophysiology experiments demonstrated that repellent exposure disrupts ionic channel activity and modifies neuronal synapse and energy production processes.

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The Aedes aegypti mosquito is the main hematophagous vector responsible for arbovirus transmission in Brazil. The disruption of A. aegypti hematophagy remains one of the most efficient and least toxic methods against these diseases and, therefore, efforts in the research of new chemical entities with repellent activity have advanced due to the elucidation of the functionality of the olfactory receptors and the behavior of mosquitoes. With the growing interest of the pharmaceutical and cosmetic industries in the development of chemical entities with repellent activity, computational studies (e.g., virtual screening and molecular modeling) are a way to prioritize potential modulators with stereoelectronic characteristics (e.g., pharmacophore models) and binding affinity to the AaegOBP1 binding site (e.g., molecular docking) at a lower computational cost. Thus, pharmacophore- and docking-based virtual screening was employed to prioritize compounds from Sigma-Aldrich® (n = 126,851) and biogenic databases (n = 8766). In addition, molecular dynamics (MD) was performed to prioritize the most potential potent compounds compared to DEET according to free binding energy calculations. Two compounds showed adequate stereoelectronic requirements (QFIT > 81.53), AaegOBP1 binding site score (Score > 42.0), volatility and non-toxic properties and better binding free energy value (∆G < −24.13 kcal/mol) compared to DEET ((N,N-diethyl-meta-toluamide)) (∆G = −24.13 kcal/mol).

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DEET is considered the gold standard for insect repellent products. However, it behaves as a strong skin permeant. DEET was encapsulated in Solid Lipid Microparticles (SLM) and characterized in terms of morphology, particle size, cytotoxicity and ex vivo permeation. The particles exhibited micrometric size with a spherical shape. In addition, we developed and validated an analytical method for DEET quantification by high performance liquid chromatography (HPLC), which was selective, linear, precise, accurate and robust. The toxicity test in cell culture of keratinocytes, fibroblasts and macrophages showed that the formulation did not present cytotoxicity. The SLM were able to decrease the skin permeation of DEET in relation to the free active in ethanol with gain in the safe. Microparticles were able to increase the skin retention of DEET, which can contribute to extend the time of repellent action. The results showed that Solid Lipid Microparticles are safe and promising topical formulation to insect bite prevention.

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One of the main vectors for malaria in Latin America is Anopheles pseudopunctipennis (Theobald), whereas Aedes aegypti (L.) is the primary vector of dengue, yellow fever, Zika and chikungunya viruses. The use of repellents is recommended as a personal protection method against these mosquitoes. However there are very few studies evaluating the effect of repellents on An. pseudopunctipennis. The use of a Petri dish to study repellence has been applied by several authors on flies, cockroaches, kissing bugs and mosquitoes, being a valuable technique for species that are difficult to breed under laboratory conditions, such as An. pseudopunctipennis. In the present study, we evaluated the repellence of the essential oil of the Eucalyptus nitens (Shining gum), its main component (1,8-cineole) and the commercial repellent DEET on An. pseudopunctipennis and Ae. aegypti adult females using the plaque repellency method coupled to EthoVision XT10.1 video-tracking software. Repellent effect and locomotor activity were studied through a repellence index (RI) together with an axis constructed from the behavioural variables obtained using the tracking software. DEET repellent effect was observed at 0.01 mg/mL for Ae. aegypti and 0.01 and 0.1 mg/mL for An. pseudopunctipennis. In addition, the essential oil showed significant repellence at 1 and 10 mg/mL for Ae. aegypti, and 1, 5, 10 and 25 mg/mL for An. pseudopunctipennis. Neither of these species were repelled at any concentration of 1,8-cineole. This is the first study that evaluates these compounds on An. pseudopunctipennis females and quantifies their effects on the activity of both species.

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Insecticides and repellents are routinely used in Brazil because of the high rates of arbovirus transmission and the nuisance caused by mosquitoes. However, few studies have assessed the effectiveness of repellents against mosquito populations that have been under exposure to xenobiotics, mainly insecticides and repellents. This study investigated the sensitivity of a field population of Aedes aegypti (Linnaeus, 1762) from a dengue-endemic area under high insecticide pressure to N,N-diethylmethylbenzamide (DEET), the active ingredient in common repellent products. The field (Laranjeiras, Sergipe, Brazil) and laboratory (Rockefeller) populations were characterized for the presence of the Val1016Ile kdr mutation, associated with pyrethroid resistance, and locomotor activity. Repellency bioassays were performed to assess the response of the mosquitoes to human odor by exposing them to 10% DEET applied to the skin in ethanol. Samples from the field population showed higher frequency of the kdr mutation, 21.9% homozygous and 21.9% heterozygous, greater locomotor activity and greater sensitivity to DEET than the laboratory population. These results suggest increased sensitivity to DEET in field populations and a possible interaction between insecticide exposure and sensitivity to DEET.

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A total of 115 aryl amides were synthesized and screened for vapor repellency against the Orlando (OR) strain of Aedes aegypti mosquitoes. Of these compounds, 29 had 1 h repellency EC50 values comparable to or better than N,N-diethyl-meta-toluamide (DEET, 1 h EC50 value of 35 µg/cm2), with 2,2,3,3,3-pentafluoro-N-(4-fluorophenyl)propenamide (53) and 2,2,3,3,4,4,4-heptafluoro-N-(3,4,5-trifluorophenyl)butanamide (101) exhibiting the most potent EC50 values of 4.5 and 2.9 µg/cm2, respectively. The cross-resistance of select, highly potent, derivatives against the pyrethroid-resistant Puerto Rico (PR) strain of A. aegypti was also investigated, and little to no resistance was observed. When synergized with 1R-trans-permethrinic acid (TFA), compound 101 had a 1 h EC50 value 6 times lower than metofluthrin against OR and 40 times lower against PR mosquitoes. Additionally, preliminary mammalian oral toxicity was screened for compounds 69 and 101, and both exhibited LD50 values of >2000 mg/kg. The structure-activity relationship analysis, which guided the synthesis of these derivatives, is given, and key trends are highlighted to inform future analogue design.

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The German cockroach, Blattella germanica L., is a hemimetabolous insect pest of economical and medical importance. N,N-diethyl-3-methylbenzamide (DEET) is an insect repellent whose effect on this species has received very little attention. The objective of this work was to determine whether the behavioral response of B. germanica to DEET varies along its life cycle. DEET repellence was assessed in small, medium, and large nymphs, and in adults of both sexes, all originated from the same laboratory colony (CIPEIN). The experimental arena consisted in a piece of filter paper treated with repellent on one half (195 µg/cm2) and solvent alone on the other half. A cockroach was placed on the filter paper, and its behavior was filmed. An image analyzer was used to quantify how long the insect spent on each side of the paper. As a control, a cockroach was exposed to a piece of filter paper treated with solvent (acetone) alone. Each assay was repeated independently six times. Distribution coefficient (DC) values were calculated, a parameter that ranges between 0 (attraction) and 1 (repellence). Small nymphs were more sensitive to DEET (mean DC = 0.93). The mean DC values of the other groups varied between 0.62 (medium nymphs) and 0.71 (male adults). The group of medium nymphs was the only one whose behavior was not significantly altered by exposure to DEET. The results show the importance of assessing insect repellents at different stages of the insect's life cycle in order to obtain a complete panorama of its effect.

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The present study aimed to evaluate the behaviour of larvae of Rhipicephalus microplus exposed to different stimuli. A Y-olfactometer was positioned vertically and R. microplus larvae were exposed to environmental air, CO2 alone, N,N-diethyl-3-methylbenzamide (DEET) alone, and CO2 combined with the repellents DEET and (E)-2-octenal. Tests were also conducted with the olfactometer positioned horizontally; in this case, however, only CO2 was tested. In all tests conducted with the Y-olfactometer positioned vertically, CO2 activated R. microplus larvae even in the presence of DEET and (E)-2-octenal, although activation was lower when these repellents were used. In the absence of CO2 , larval behaviour against DEET was similar to that of the larvae in the control group. In the tests performed with the olfactometer positioned horizontally, the larvae had no significant response to the presence of CO2 . The larvae were not attracted to or repelled by any compound tested in either the vertical or horizontal position of the olfactometer. The lack of horizontal displacement, attraction or repellence may have been a result of the ambush behaviour of this tick species. However, when larvae were exposed to stimuli and the olfactometer was positioned vertically, the interference of attractant and repellent stimuli in larval behaviour was assessed.

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Aedes aegypti é um mosquito de grande interesse para saúde pública, pois é o vetor de arbovírus, como dengue, chikungunya e Zika. Para o controle desse vetor, são utilizados o controle biológico, mecânico e o controle químico, com utilização de inseticidas e repelentes. Os repelentes são considerados uma das melhores formas de se evitar as picadas das fêmeas, sendo os mais comercializados aqueles que possuem N,N-dietilmetilbenzamida (DEET) na fórmula, além de serem um dos mais estudados atualmente. Entretanto a resitência a alguns inseticidas como o piretroide, pode levar à alteração na atividade locomotora dos mosquitos. Deste modo, o presente trabalho tem como objetivo avaliar aspectos relacionados à tolerância ao DEET e à resistência a xenobióticos em cepas Ae. aegypti de campo (Laranjeiras) e de laboratório (Rockefeller). Foram realizados testes de repelência com Ae. aegypti para a resposta ao odor humano. Em cada teste, foram utilizadas 50 fêmeas, totalizando 700 fêmeas da população Laranjeiras e 1500 fêmeas para a população Rockefeller. As fêmeas foram colocadas em gaiolas de teste por cerca de duas horas, a fim de se adaptarem ao ambiente. Posteriormente, foi realizado o teste de repelência, que consistiu na exposição do mosquito a 0,5 mL de DEET (10% em etanol), este foi aplicado uniformemente pelo antebraço humano. Para diagnosticar a presença da mutação kdr na população de Laranjeiras foram analisadas 32 fêmeas dessa população. Para avaliar a atividade locomotora das fêmeas de Ae. aegypti Rockefeller e de Laranjeiras, foi utilizado o Drosophila Activity Monitor - Trikinetics. No período de setembro a novembro de 2019, foram instaladas 290 ovitrampas no município de Laranjeiras - SE, tendo sido verificado um total de 80,3% de palhetas com presença de ovos de Aedes, contabilizando 15.940 ovos. Após a realização dos bioensaios, foi possivel observar maior sensibilidade ao DEET nas fêmeas provinientes do campo. Além disso, também foi possivel observar a presença da mutação kdr e uma maior atividade locomotora nessa população. Dessa forma, nossos resultados sugerem que mosquitos resistentes podem ser mais suceptíveis ao DEET.

Aedes aegypti is a mosquito of great interest for public health, as it is the vector of arboviruses, such as dengue, chikungunya and Zika. Biological, mechanical and chemical control, with the use of insecticides and repellents, are used against this vector. Repellents are considered one of the best ways to avoid female bites, being those that have N, N-diethylmethylbenzamide (DEET) in the formula the most commercialized, as well as the most studied today. However, resistance to some insecticides such as pyrethroid, can lead to changes in the locomotor activity of mosquitoes. Thus, this study aims to evaluate aspects related to DEET tolerance and resistance to xenobiotics in field Ae. aegypti (Laranjeiras) and laboratory (Rockefeller) strains. Repellency tests were performed with Ae. aegypti for the response to human odor. In each test, 50 females were used, totaling 700 females from the Laranjeiras population and 1500 females from the Rockefeller population. The females were placed in test cages for about two hours in order to adapt to the environment. Subsequently, the repellency test was performed, which consisted of exposing the mosquito to 0.5 mL of DEET (10% in ethanol), which was applied evenly to the human forearm. To diagnose the presence of the kdr mutation in the population of Laranjeiras, 32 females from that population were analyzed. To evaluate the locomotor activity of Ae. aegypti Rockefeller and Laranjeiras females,, the Drosophila Activity Monitor - Trikinetics was used. In the period from September to November 2019, 290 ovitraps were installed in the municipality of Laranjeiras - SE, with a total of 80.3% of reeds with the presence of Aedes eggs, accounting for 15,940 eggs. After conducting the bioassays, it was possible to observe greater sensitivity to DEET in females from the field. In addition, it was also possible to observe the presence of the kdr mutation and greater locomotor activity in this population. Thus, our results suggest that resistant mosquitoes may be more susceptible to DEET.

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