The insecticide ß-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype.

ß-Cyfluthrin, a class II Pyrethroid, is an insecticide used worldwide in agriculture, horticulture (field and protected crops), viticulture, and domestic applications. ß-Cyfluthrin may impair the function of biological systems; however, little information is available about its potential cardiotoxic effect. Here, we explored the acute toxicity of ß-Cyfluthrin in isolated heart preparations and its cellular basis, using isolated cardiomyocytes. Moreover, ß-Cyfluthrin effects on the sodium current, especially late sodium current (INa-L), were investigated using human embryonic kidney cells (HEK-293) cells transiently expressing human NaV1.5 channels. We report that ß-Cyfluthrin raised INa-L in a dose-dependent manner. ß-Cyfluthrin prolonged the repolarization of the action potential (AP) and triggered oscillations on its duration. Cardiomyocytes contraction and calcium dynamics were disrupted by the pesticide with a marked incidence of non-electronic-stimulated contractions. The antiarrhythmic drug Ranolazine was able to reverse most of the phenotypes observed in isolated cells. Lastly, ventricular premature beats (VPBs) and long QT intervals were found during ß-Cyfluthrin exposure, and Ranolazine was able to attenuate them. Overall, we demonstrated that ß-Cyfluthrin can cause significant cardiac alterations and Ranolazine ameliorated the phenotype. Understanding the insecticides' impacts upon electromechanical properties of the heart is important for the development of therapeutic approaches to treat cases of pesticides intoxication.

Metabolism of bifenthrin, ß-cyfluthrin, λ-cyhalothrin, cyphenothrin and esfenvalerate by rat and human cytochrome P450 and carboxylesterase enzymes.

The metabolism of bifenthrin (BIF), ß-cyfluthrin (CYFL), λ-cyhalothrin (CYHA), cyphenothrin (CYPH) and esfenvalerate (ESF) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 90, 21 and 15 days and from adult humans. Pyrethroid metabolism was also studied with some human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. All five pyrethroids were metabolised by adult (90 day old) rat hepatic microsomal CYP and CES enzymes and by cytosolic CES enzymes. The pyrethroids were also metabolised by human liver microsomes and cytosol. Some species differences were observed. Pyrethroid metabolism by cytosolic CES enzymes contributes to the overall hepatic clearance of these compounds. CYFL, CYHA, CYPH and ESF were metabolised by rat plasma CES enzymes, whereas none of the pyrethroids were metabolised by human plasma. This study demonstrates that the ability of male rats to metabolise these pyrethroids by hepatic CYP and CES enzymes and plasma CES enzymes increases with age. In all instances, apparent intrinsic clearance values were lower in 15 than in 90 day old rats. All pyrethroids were metabolised by some of the human expressed CYP enzymes studied and apart from BIF were also metabolised by CES enzymes.

Effect of ß-cyfluthrin (synthetic pyrethroid) on learning, muscular coordination and oxidative stress in Swiss albino mice.

The present study was planned to evaluate neurotoxic effects of ß-cyfluthrin in female Swiss albino mice. Two doses of ß-cyfluthrin, specifically, one-tenth of median lethal dose (LD50) and one-twentieth of LD50, were selected for the study. Open-field behaviour, exploratory behaviour and emotional status were affected, and animals showed anxiety-like behaviour after ß-cyfluthrin administration. Spatial learning was decreased using the Hebb-Wiliams maze. Acetylcholinesterase enzyme activity significantly decreased in the treated animals. The administration of ß-cyfluthrin caused increased lipid peroxidation (malondialdehyde) and decreased superoxide dismutase, catalase and glutathione peroxidase activity in brain tissue. In conclusion, ß-cyfluthrin caused neurotoxicity as well as oxidative damage in the brain of Swiss albino mice at the tested dose levels.

In vitro cytotoxicity and genotoxicity of Furia®180 SC (zeta-cypermethrin) and Bulldock 125®SC (ß-cyfluthrin) pyrethroid insecticides in human peripheral blood lymphocytes.

In the present study, human peripheral blood lymphocytes were exposed in vitro to 0, 6, 12, 18, 24, and 30 µg/mL Furia®180 SC (zeta-cypermethrin) and 0, 6.3, 12.5, 18.8, 25, and 31.3 µg/mL Bulldock®125 SC (ß-cyfluthrin). Exposure to 32 µg/mL bleomycin for 24 h served as a positive control. The cytotoxic and genotoxic effects of each insecticide were analyzed using alkaline comet and trypan blue dye exclusion assays. DNA damage was evaluated through three genotoxicity parameters: tail length (TL), tail moment (TM) and tail intensity (TI). Furia®180 SC and Bulldock®125 SC pyrethroid insecticides and bleomycin significantly increased DNA damage in a concentration-dependent manner. Bulldock®125 SC induced more DNA damage than Furia. Lymphocyte viability did not change after exposure to different concentrations of the two pyrethroid insecticides and bleomycin. Moreover, genotoxic results demonstrated that Furia®180 SC and Bulldock®125 SC insecticides caused in vitro DNA damage in human peripheral lymphocytes.

Pyrethroid residue dynamics in insects depends on the circadian clock.

Many factors may affect pesticide effectiveness against pests. One of the factors that should be considered is circadian rhythmicity. In this study, we evaluated daily variations in pyrethroid susceptibility in the house cricket, Acheta domesticus L. Crickets were exposed to a standard dose of ß-cyfluthrin at different times of a day, and pesticide residue levels were evaluated using gas chromatography. Results demonstrate that the time of pyrethroid disappearance is correlated with the circadian clock, with the highest decomposition rate at night. Furthermore, crickets also showed the highest resistance to the insecticide at night, expressed as a high survival rate. Moreover, ß-cyfluthrin induced significant changes in thermal preferences of intoxicated crickets. This is the first report showing that pyrethroid residue levels in the crickets' body depend on its circadian clock.

Risk assessment of ß-cyfluthrin and imidacloprid in chickpea pods and leaves.

Dissipation of ß-cyfluthrin and imidacloprid in chickpea pods and leaves was measured following three applications of Solomon 300 OD (ß-cyfluthrin 9 percent +imidacloprid 21 percent) at 200 and 400mLha(-1). Residues of ß-cyfluthrin on chickpea pods and leaves were found to be below its limit of quantification (LOQ) of 0.01mgkg(-1) after 7 days at both the dosages. Similarly, imidacloprid residues were found to be below its LOQ of 0.01mgkg(-1) at 10 days. Half-life periods on chickpea pods and leaves for ß-cyfluthrin were found to be 1.06 and 0.58 days, whereas for imidacloprid these values were observed to be 2.07 and 1.75 days at recommended dose. As the theoretical maximum residue contributions on chickpea pods and leaves are found to be less than the maximum permissible intake values even on 0 day, therefore consumer health risks are minimal at both the dosages on chickpea.

Identification of two ABCC transporters involved in malathion detoxification in the red flour beetle, Tribolium castaneum.

ABC transporters have been suggested to be involved in insecticide detoxification in different insect species mainly based on the indirect observation of transcriptional upregulation of ABC gene expression in response to insecticide exposure. Previous studies performed by us and others in the red flour beetle, Tribolium castaneum, have analyzed the function of TcABCA-C and TcABCG-H genes using RNA interference (RNAi) and demonstrated that specific TcABCA and TcABCC genes are involved in the elimination of the pyrethroid tefluthrin and the benzoylurea diflubenzuron, because gene silencing increased the beetle's susceptibility to the insecticides. In this study, we focused on the potential functions of TcABCA-C genes in detoxification of the pyrethroid cyfluthrin (CF), the organophosphate malathion (MAL) and the diacylhdyazine tebufenozide (TBF). Analysis of transcript levels of selected TcABCA-C genes in response to treatment with these three chemically unrelated insecticides revealed that some genes were particularly upregulated after insecticide treatment. In addition, the ABC inhibitor verapamil synergized significantly the toxicity of MAL but only negligibly CF and TBF toxicities. Finally, silencing of two TcABCC genes by RNAi revealed a significant increase in susceptibility to MAL. In contrast, we did not observe a significant increase in insecticide-induced mortalities when knocking down TcABC genes in larvae treated with CF or TBF, although they were upregulated in response to insecticide treatment. Our results suggest that two pleiotropic ABCC transporters expressed in metabolic and excretory tissues contribute to the elimination of MAL.

Crystallography of Contemporary Contact Insecticides.

The active forms of contact insecticides used for combatting mosquito-borne infectious diseases are typically crystalline solids. Numerous molecular crystals are polymorphic, crystallizing in several solid forms characterized by different physicochemical properties, including bioavailability. Our laboratory recently found that the activity of crystalline contact insecticides is inversely dependent on the thermodynamic stability of their polymorphs, suggesting that efficacy can be enhanced by the manipulation of the solid-state structure. This paper argues that crystallography should be central to the development of contact insecticides, particularly because their efficacy continues to be compromised by insecticide resistance, especially among Anopheles mosquito populations that spread malaria. Although insecticidal compounds with new modes of action have been introduced to overcome resistance, new insecticides are expensive to develop and implement. The repurposing of existing chemical agents in metastable, more active crystalline forms provides an inexpensive and efficient method for 'evergreening' compounds whose risks are already well-established. We report herein seven new single-crystal structures of insecticides used for controlling infectious disease vectors. The structures reported herein include pyrethroid insecticides recommended by the WHO for indoor residual spraying (IRS)-bifenthrin, ß-cyfluthrin, etofenprox, α-cypermethrin, and λ-cyhalothrin as well as the neonicotinoid insecticide thiacloprid.

Ocimum basilicum Essential Oil Modulates Hematotoxicity, Oxidative Stress, DNA Damage, and Cell Cycle Arrest Induced by ß-cyfluthrin in Rat Liver.

Pesticides are used in large quantities infrequently, resulting in environmental damage and health issues. The goal of the current study was to explore the ameliorating effect of Ocimum basilicum (Basil) leaves essential oil versus the harmful effects of ß-cyfluthrin in rat liver. Male Wistar rats were classified at random into four groups; negative control (corn oil), basil leaves essential oil (BEO, 3 ml/kg), ß-cyfluthrin (positive control) (ß-Cyf; 15 mg/kg BW, 1/25 LD50), and BEO plus ß-Cyf, respectively. The rats were given their doses orally every day for a month. Results revealed that BEO yielded 6.32 mg/g with 33 identified components, representing 97% of the total oil. BEO implicated a considerable level of total phenolic contents, DPPH radical scavenging capacity, ABTS activity, and FRAP. The treatment of ß-Cyf dramatically elevated lipid peroxidation (TBARS and H2O2) (LPO), protein oxidation (PC, AOPP, and HYP), and considerably reduced enzymatic (SOD, CAT, GPx, GR, and GST) and non-enzymatic (GSH) antioxidants. After ß-Cyf treatment, hematological parameters, body and liver weights, enzyme activity (AST, ALT, ALP, and LDH), as well as protein, albumin, globulin, and total bilirubin levels were all considerably affected. Furthermore, ß-Cyf increased the expression of pro-inflammatory genes (TNF-α, IL-6) as well as DNA damage and cell cycle arrest in the G0/G1 phase and decreased the number of cells in S and G2/M phase of liver cells. Moreover, rats given BEO then intoxicated with ß-Cyf showed substantial changes in the majority of the parameters tested. Finally, BEO was shown to have high antioxidant efficacy in combating ß-Cyf toxicity because of its high phenolic content.

Functional analysis of ABCG and ABCH transporters from the red flour beetle, Tribolium castaneum.

BACKGROUND: ATP-binding cassette transporter (ABC transporter) subfamilies ABCA-C and ABCG-H have been implicated in insecticide detoxification, mostly based on findings of elevated gene expression in response to insecticide treatment. We previously characterized TcABCA-C genes from the model beetle and pest Tribolium castaneum and demonstrated that TcABCA and TcABCC genes are involved in the elimination of diflubenzuron, because RNA interference (RNAi)-mediated gene silencing increased susceptibility. In this study, we focused on the potential functions of TcABCG and TcABCH genes in insecticide detoxification. RESULTS: When we silenced the expression of TcABCG-H genes using RNAi, we noticed a previously unreported developmental RNAi phenotype for TcABCG-4F, which is characterized by 50% mortality and ecdysial arrest during adult moult. When we knocked down the Drosophila brown orthologue TcABCG-XC, we did not obtain apparent eye colour phenotypes but did observe a loss of riboflavin uptake by Malpighian tubules. Next, we determined the expression profiles of all TcABCG-H genes in different tissues and developmental stages and analysed transcript levels in response to treatment with four chemically unrelated insecticides. We found that some genes were specifically upregulated after insecticide treatment. However, when we determined insecticide-induced mortalities in larvae that were treated by double-stranded RNA injection to silence those TcABCG-H genes that were upregulated, we did not observe a significant increase in susceptibility to insecticides. CONCLUSION: Our findings suggest that the observed insecticide-dependent induction of TcABCG-H gene expression reflects an unspecific stress response, and hence underlines the significance of functional studies on insecticide detoxification. © 2021 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Impacts of Dietary Phytochemicals in the Presence and Absence of Pesticides on Longevity of Honey Bees (Apis mellifera).

Because certain flavonols and phenolic acids are found in pollen and nectar of most angiosperms, they are routinely ingested by Apis mellifera, the western honey bee. The flavonol quercetin and the phenolic acid p-coumaric acid are known to upregulate detoxification enzymes in adult bees; their presence or absence in the diet may thus affect the toxicity of ingested pesticides. We conducted a series of longevity assays with one-day-old adult workers to test if dietary phytochemicals enhance longevity and pesticide tolerance. One-day-old bees were maintained on sugar syrup with or without casein (a phytochemical-free protein source) in the presence or absence of quercetin and p-coumaric acid as well as in the presence or absence of two pyrethroid insecticides, bifenthrin and ß-cyfluthrin. Dietary quercetin (hazard ratio, HR = 0.82), p-coumaric acid (HR = 0.91) and casein (HR = 0.74) were associated with extended lifespan and the two pyrethroid insecticides, 4 ppm bifenthrin (HR = 9.17) and 0.5 ppm ß-cyfluthrin (HR = 1.34), reduced lifespan. Dietary quercetin enhanced tolerance of both pyrethroids; p-coumaric acid had a similar effect trend, although of reduced magnitude. Casein in the diet appears to eliminate the life-prolonging effect of p-coumaric acid in the absence of quercetin. Collectively, these assays demonstrate that dietary phytochemicals influence honey bee longevity and pesticide stress; substituting sugar syrups for honey or yeast/soy flour patties may thus have hitherto unrecognized impacts on adult bee health.

Curcumin modulates oxidative stress and genotoxicity induced by a type II fluorinated pyrethroid, beta-cyfluthrin.

Present study examines the possibility of ß-cyfluthrin (ß-CYF) induced oxidative stress, genotoxicity, histopathological alterations and the role of curcumin (CUR) in alleviating its toxic effects. CUR is a naturally occurring phenolic compound of turmeric (Curcuma longa) and is used as a spice, food-coloring agent and in cosmetics and medicines. CUR provides vital protection against many pathological conditions due to its antioxidant and anti-inflammatory properties. Male Swiss albino mice were distributed into six groups, I: control, II: CUR (0.2%), III: ß-CYF low dose (1/20 of LD50), IV: ß-CYF high dose (1/10 of LD50), V: ß-CYF low dose + CUR and VI: ß-CYF high dose + CUR. Mice were orally administered their respective doses daily for 21 days. ß-CYF caused elevation in AST, ALT, LPO and decline in GPx, CAT and SOD activities. A significant decrease in MI and increase in chromosomal aberrations, TL, TI and TM was recorded in ß-CYF exposed groups. CUR co-administration modulated AST, ALT, LPO, GPx, CAT and SOD activity. CUR supplementation improved the MI and reduced the chromosomal aberrations, TL, TI and TM. ß-CYF caused serious pathological alterations in liver and these were alleviated by CUR. It is concluded that CUR scavenges ROS and renders a protection against ß-CYF genotoxicity.