GPR39-mediated ERK1/2 signaling reduces permethrin-induced proliferation of estrogen receptor α-negative cells.

Certain insecticides are known to have estrogenic effects by activating estrogen receptors through genomic transcription. This has led researchers to associate specific insecticide use with an increased breast cancer risk. However, it is unclear if estrogen receptor-dependent pathways are the only way in which these compounds induce carcinogenic effects. The objective of this study was to determine the impact of the pyrethroid insecticide permethrin on the growth of estrogen receptor negative breast cancer cells MDA-MB-231. Using tandem mass spectrometric techniques, the effect of permethrin on cellular protein expression was investigated, and gene ontology and pathway function enrichment analyses were performed on the deregulated proteins. Finally, molecular docking simulations of permethrin with the candidate target protein was performed and the functionality of the protein was confirmed through gene knockdown experiments. Our findings demonstrate that exposure to 10-40 µM permethrin for 48 h enhanced cell proliferation and cell cycle progression in MDA-MB-231. We observed deregulated expression in 83 upregulated proteins and 34 downregulated proteins due to permethrin exposure. These deregulated proteins are primarily linked to transmembrane signaling and chemical carcinogenesis. Molecular docking simulations revealed that the overexpressed transmembrane signaling protein, G protein-coupled receptor 39 (GPR39), has the potential to bind to permethrin. Knockdown of GPR39 partially impeded permethrin-induced cellular proliferation and altered the expression of proliferation marker protein PCNA and cell cycle-associated protein cyclin D1 via the ERK1/2 signaling pathway. These findings offer novel evidence for permethrin as an environmental breast cancer risk factor, displaying its potential to impact breast cancer cell proliferation via an estrogen receptor-independent pathway.

In-vivo and in-silico studies to identify toxicity mechanisms of permethrin with the toxicity-reducing role of ginger.

In this study, the toxic effects of permethrin on Allium cepa L. and the protective role of Zingiber officinale rhizome extract (Zoex) were investigated. In this context, 6 different groups were formed. While the control group was treated with tap water, the groups II and III were treated with 10 µg/mL and 20 µg/mL Zoex, respectively, and the group IV was treated with 100 µg/L permethrin. The protective effect of Zoex against permethrin toxicity was studied as a function of dose, and groups V and VI formed for this purpose were treated with 10 µg/mL Zoex + 100 µg/L permethrin and 20 µg/mL Zoex + 100 µg/L permethrin, respectively. After 72 h of germination, cytogenetic, biochemical, physiological, and anatomical changes in meristematic cells of A. cepa were studied. As a result, permethrin application decreased the mitotic index (MI) and increased the frequency of micronuclei (MN), and chromosomal abnormalities. The increase in malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) and the decrease in glutathione (GSH) indicate that permethrin causes oxidative damage. Compared to the control group, a 68.5% decrease in root elongation (p < 0.05) and an 81.8% decrease (p < 0.05) in weight gain were observed in the permethrin-treated group. It was found that the application of Zoex together with permethrin resulted in regression of all detected abnormalities, reduction in the incidence of anatomical damage, MN and chromosomal aberrations, and improvement in MI rates. The most significant improvement was observed in group VI treated with 20 µg/mL Zoex, and Zoex was also found to provide dose-dependent protection. The toxicity mechanism of permethrin was also elucidated by molecular docking and spectral studies. From the data obtained during the study, it was found that permethrin has toxic effects on A. cepa, a non-target organism, while Zoex plays a protective role by reducing these effects.

Adult Mosquito and Butterfly Exposure to Permethrin and Relative Risk Following ULV Sprays from a Truck-Mounted Sprayer.

Ground applications of adulticides via a specialized truck-mounted sprayer are one of the most common practices for control of flying adult mosquitoes. Aerosols released to drift through a targeted area persist in the air column to contact and kill flying mosquitoes, but may also drift into adjacent areas not targeted by the applications where it may affect nontarget insects such as imperiled butterflies. This study compared the risk of permethrin to adult mosquitoes and adult butterflies to assess the likelihood that the butterflies would be affected following such sprays. Permethrin toxicity values were determined for Aedes aegypti and Culex quinquefasciatus (LD50s of 81.1 and 166.3 ng/g dw, respectively) and then combined with published toxicity data in a species sensitivity distribution for comparison with published permethrin toxicity data for adult butterflies. The sensitivity distributions indicated adult butterflies and mosquitoes are similarly sensitive, meaning relative risk would be a function of exposure. Exposure of adult butterflies and adult mosquitoes to permethrin was measured following their exposure to ULV sprays in an open field. Average permethrin concentrations on adult mosquitoes (912-38,061 ng/g dw) were typically an order of magnitude greater than on adult butterflies (110-11,004 ng/g dw) following each spray, indicating lower risk for butterflies relative to mosquitoes. Despite lower estimated risk, 100% mortality of adult butterflies occurred following some of the sprays. Additional studies could help understand exposure and risk for butterflies in densely vegetated habitats typical near areas treated by ULV sprays.

Delineating involvement of MAPK/NF-κB pathway during mitigation of permethrin-induced oxidative damage in fish gills by melatonin.

Present study evaluated involvement of transcription factors during permethrin-induced gill toxicity and its amelioration by melatonin. First, adult Notoptertus notopterus females were exposed to permethrin at nominal concentrations [C: 0.0, P1: 0.34, P2: 0.68 µg/L] for 15 days followed by intramuscular melatonin administration (100 µg/kg body weight) for 7 days. Gill MDA, XO, LDH levels increased, while Na+-K+-ATPase, SDH, cytochrome C oxidase levels decreased with increasing permethrin concentrations. Glutathione, SOD, CAT, GST, GRd levels increased in P1 than C, but decreased in P2 than P1, C. Melatonin administration restored gill enzyme and antioxidant levels in P1, P2. Next, isolated gill tissues were exposed to permethrin at 25, 50 µM doses along with melatonin administration (100 µg/mL). NF-κB, NRF2, Keap1, ERK, Akt, caspases protein expression changed significantly during permethrin-induced gill damage. Melatonin administration amended permethrin-induced molecular imbalance through modulation of caspase proteins and MAPK/NF-κB signal transduction pathway via melatonin receptor 1.

Time-series analysis of transcriptomic changes due to permethrin exposure reveals that Aedes aegypti undergoes detoxification metabolism over 24 h.

Insecticide resistance is a multifaceted response and an issue across taxa. Aedes aegypti, the mosquito that vectors Zika, dengue, chikungunya, and yellow fever, demonstrates high levels of pyrethroid resistance across the globe, presenting a challenge to public health officials. To examine the transcriptomic shifts across time after exposure to permethrin, a 3'Tag-Seq analysis was employed on samples 6, 10, and 24 h after exposure along with controls. Differential expression analysis revealed significant shifts in detoxifying enzymes and various energy-producing metabolic processes. These findings indicate significant alterations in gene expression associated with key energy mobilization pathways within the system. These changes encompass a coordinated response involving lipolysis, beta-oxidation, and the citric acid cycle, required for the production of energetic molecules such as ATP, NADH, NADPH, and FADH. These findings highlight a complex interplay of metabolic processes that may have broader implications for understanding insect physiology and response to environmental stimuli. Among the upregulated detoxifying enzymes are cytochrome P450s, glutathione s-transferases and peroxidases, and ATP-binding cassette transporters. Additionally, eight heat shock genes or genes with heat shock domains exhibit the highest fold change across time. Twenty-four hours after exposure, samples indicate a global downregulation of these processes, though principal component analysis suggests lasting signatures of the response. Understanding the recovery response to insecticide exposure provides information on possible new genetic and synergist targets to explore.

Toxic effects of the synthetic pyrethroid permethrin on the hematological parameters and antioxidant enzyme systems of the freshwater fish Cyprinus carpio L.

This study investigated changes in hematological and antioxidant parameters of carp exposed to two different doses of synthetic pyrethroid permethrin (control, vehicle, 10 ppm, and 20 ppm) for two different periods (4 days and 21 days). Hematological analyses were then performed on a veterinary Ms4 (Melet Schloesing, France) blood counter using commercially available kits (Cat. No. WD1153). Buege and Aust for MDA, Luck for CAT, McCord and Frivovich for SOD, Lawrence and Burk methods for GSH-Px were used to determine antioxidant parameters. Decreases in RBC count, Hb amount, Hct value, granulocyte ratios, and increases in total WBC and lymphocyte ratios were statistically significant in both dose groups treated with permethrin compared to the control group (p < 0.05). However, there was no statistically significant difference in monocyte ratios (p > 0.05). Overall, permethrin exposure caused an increase in MDA levels in the liver and gill tissues of carp in both dose and duration groups compared to the control group. Also, no statistically significant difference between the two dose groups in the liver tissue was observed in terms of duration (p > 0.05). Nonetheless, the increase in MDA levels in PERM10 and PERM20 dose groups in the gill tissues over 21 days was statistically significant (p < 0.05). Furthermore, permethrin exposure increased CAT, SOD, and GSH-Px enzyme activities in the gill tissue, while impacting in the opposite direction the liver tissue. Finally, regarding MDA, CAT, SOD, and GSH-Px levels, the control, and control acetone dose groups of all experimental groups were observed to be similar (p > 0.05). As a result, permethrin produced a toxic effect on Cyprinus carpio, triggering changes in blood parameters and inducing the antioxidant enzyme system.

Early-life exposure to permethrin affects phenotypic traits in both larval and adult mangrove rivulus Kryptolebias marmoratus.

In fishes, the impacts of environmental constraints undergone during development on the behavioural response of individuals are not well understood. Obtaining more information is important since the aquatic environment is widely exposed to pollution involving neurotoxic compounds likely to cause phenotypic changes that can affect animal fitness. We explored how early exposure to the pyrethroid insecticide permethrin (PM), a compound known for its neurotoxicity, influences the phenotypic traits in both larvae and adults of the self-fertilizing fish mangrove rivulus, Kryptolebias marmoratus. First, we investigated immediate effects of PM on larvae after one-week exposure (0-7 days post-hatching): larvae exposed to high concentration (200 µg.L-1) grew less, were less active, had negative thigmotaxis and were less likely to capture prey than control individuals and those exposed to low concentration (5 µg.L-1). No difference was found between treatments when considering oxygen consumption rate and cortisol levels. Persistent effects of early exposure to PM on adults (147-149 days post-hatching) showed that fish previously exposed to high concentration of PM overcompensated growth, leading them to finally be longer and heavier than fish from other treatments. Moreover, we evidenced that levels of cortisol interacted with early PM exposure to affect behaviours during dyadic contests. Fish were more likely to initiate fighting behaviours and were more likely to be aggressive when they have low pre-contest levels of cortisol, but these effects were less pronounced when individuals were exposed to PM. This study shows that PM can have both immediate and persistent effects on phenotypic traits in a self-fertilizing vertebrate and suggests that a pyrethroid can interact with hormones action to affect animal behaviour.

Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro.

The evidence supporting the biological plausibility of the association of permethrin and malathion with hematological cancer is limited and contradictory; thus, further studies are needed. This study aimed to investigate whether in vitro exposure to 0.1 µM permethrin and malathion at 0, 24, 48 and 72 h after cell culture initiation induced changes in the gene expression and DNA methylation in mononuclear cells from bone marrow and peripheral blood (BMMCs, PBMCs). Both pesticides induced several gene expression modifications in both tissues. Through gene ontology analysis, we found that permethrin deregulates ion channels in PBMCs and BMMCs and that malathion alters genes coding proteins with nucleic acid binding capacity, which was also observed in PBMCs exposed to permethrin. Additionally, we found that both insecticides deregulate genes coding proteins with chemotaxis functions, ion channels, and cytokines. Several genes deregulated in this study are potentially associated with cancer onset and development, and some of them have been reported to be deregulated in hematological cancer. We found that permethrin does not induce DNA hypermethylation but can induce hypomethylation, and that malathion generated both types of events. Our results suggest that these pesticides have the potential to modify gene expression through changes in promoter DNA methylation and potentially through other mechanisms that should be investigated.

Eugenol and menthol synergize the toxicity of permethrin in the blood-sucking bug, Triatoma infestans.

The blood-sucking bug, Triatoma infestans, is one of the main vectors of Chagas disease in America. It is usually controlled with pyrethroids, but the emergence of resistance to these insecticides creates the need to look for alternative products. Eugenol, menthol and menthyl acetate are botanical monoterpenes, which produce lethal and sublethal effects on insects. The purpose of this work was to determine what type of toxicological interactions occur when binary mixtures, formed by the pyrethroid permethrin and sublehtal doses of eugenol, menthol or menthyl acetate, are applied to T. infestans. First instar nymphs were exposed to filter papers impregnated with the insecticides. The number of knocked down insects was registered at different times and Knock Down Time 50% (KT50) values were calculated. The following KT50 values with their corresponding 95% Confidence Intervals were obtained: permethrin, 47.29 (39.92 - 56.32) min; permethrin + eugenol, 34.08 (29.60 - 39.01) min; permethrin + menthol, 27.54 (23.28 - 32.55) min; permethrin + menthyl acetate, 43.62 (39.99 - 47.59) min. Eugenol and menthol increased the speed of action of permethrin (synergism), but menthyl acetate had no effect on it (additivity). These results provide the basis to further explore interactions between conventional insecticides and plant monoterpenes as potential tools for controlling T. infestans.

Pyrethroid-induced oxidative stress and biochemical changes in the primary mussel cell cultures.

Pyrethroids are among the most widely used insecticides. Permethrin and tetramethrin, which are synthetic pyrethroids, are generally used to control insects in agricultural areas and household applications. Due to broad use areas, they contaminate aquatic ecosystems and cause adverse effects to the non-target aquatic organisms. Even though permethrin and tetramethrin are known to alter the oxidative stress parameters of in vivo aquatic animal model organisms, there are limited studies in vitro. This study aims to determine the adverse effects of permethrin and tetramethrin in the in vitro models of freshwater mussels exposed to 1 mg/L, 10 µg/L, 100 ng/L and 1 ng/L concentrations of chemicals for 24 h. For this purpose, reduced glutathione activities were evaluated as biomarkers of the primary gill and digestive gland cell cultures. In both cell cultures, reduced glutathione values increased in the exposed groups, compared to the control group. Even though the results showed that reduced glutathione activities had not significantly changed concentration-dependently (p > 0.05), significant differences were observed in the reduced glutathione activities of both cell cultures (p < 0.05). This study showed that permethrin and tetramethrin had highly toxic effects in the in vitro models of mussels even at low concentrations.

Pyrethroids exposure alters the community and function of the internal microbiota in Aedes albopictus.

Large amounts of insecticides bring selection pressure and then develop insecticide resistance in Aedes albopictus. This study demonstrated for the first time the effect of pyrethroid exposure on the internal microbiota in Ae. albopictus. 36, 48, 57 strains of virgin adult Ae. albopictus were exposed to the pyrethroids deltamethrin (Dme group), ß-cypermethrin (Bcy group), and cis-permethrin (Cper group), respectively, with n-hexane exposure (Hex group) as the controls (n = 36). The internal microbiota community and functions were analyzed based on the metagenomic analysis. The analysis of similarity (ANOSIM) results showed that the Hex/Bcy (p = 0.001), Hex/Cper (p = 0.006), Hex/Dme (p = 0.001) groups were well separated, and the internal microbes of Ae. albopictus vary in the composition and functions depending on the type of pyrethroid insecticide they are applied. Four short chain fatty acid-producing genera, Butyricimonas, Prevotellaceae, Anaerococcus, Pseudorhodobacter were specifically absent in the pyrethroid-exposed mosquitoes. Morganella and Streptomyces were significantly enriched in cis-permethrin-exposed mosquitoes. Wolbachia and Chryseobacterium showed significant enrichment in ß-cypermethrin-exposed mosquitoes. Pseudomonas was significantly abundant in deltamethrin-exposed mosquitoes. The significant proliferation of these bacteria may be closely related to insecticide metabolism. Our study recapitulated a specifically enhanced metabolic networks relevant to the exposure to cis-permethrin and ß-cypermethrin, respectively. Benzaldehyde dehydrogenase (EC 1.2.1.28), key enzyme in aromatic compounds metabolism, was detected enhanced in cis-permethrin and ß-cypermethrin exposed mosquitoes. The internal microbiota metabolism of aromatic compounds may be important influencing factors for pyrethroid resistance. Future work will be needed to elucidate the specific mechanisms by which mosquito microbiota influences host resistance and vector ability.

Determination of potential toxicodynamic differences of pyrethroid insecticides on native voltage-sensitive sodium channels in juvenile versus adult rat brain.

Microtransplantation of neurolemma tissue fragments from mammalian brain into the plasma membrane of Xenopus laevis oocytes is a tool to examine the endogenous structure and function of various ion channels and receptors associated with the central nervous system. Microtransplanted neurolemma can originate from a variety of sources, contain ion channels and receptors in their native configuration, and are applicable to examine diseases associated with different channelopathies. Here, we examined potential age-related differences in voltage-sensitive sodium channel (VSSC) expression and concentration-dependent responses to pyrethroids following the microtransplantation of juvenile or adult rat brain tissue (neurolemma) into X. laevis oocytes. Using automated western blotting, adult neurolemma exhibited a 2.5-fold higher level of expression of VSSCs compared with juvenile neurolemma. The predominant isoform expressed in both tissues was Nav1.2. However, adult neurolemma expressed 2.8-fold more Nav1.2 than juvenile and expressed Nav1.6 at a significantly higher level (2.2-fold). Microtransplanted neurolemma elicited ion currents across the plasma membrane of oocytes following membrane depolarization using two electrode voltage clamp electrophysiology. A portion of this current was sensitive to tetrodotoxin (TTX) and this TTX-sensitive current was abolished when external sodium ion was replaced by choline ion, functionally demonstrating the presence of native VSSC. Increasing concentrations of permethrin or deltamethrin exhibited concentration-dependent increases in inward TTX-sensitive current in the presence of niflumic acid from both adult and juvenile tissues following a pulsed depolarization of the oocyte plasma membrane. Concentration-dependent response curves illustrate that VSSCs associated with juvenile neurolemma were up to 2.5-fold more sensitive to deltamethrin than VSSCs in adult neurolemma. In contrast, VSSCs from juvenile neurolemma were less sensitive to permethrin than adult VSSCs at lower concentrations (0.6-0.8-fold) but were more sensitive at higher concentrations (up to 2.4-fold). Nonetheless, because the expected concentrations in human brains following realistic exposure levels are approximately 21- (deltamethrin) to 333- (permethrin) times below the threshold concentration for response in rat neurolemma-injected oocytes, age-related differences, if any, are not likely to be toxicologically relevant.

Impact of gulf war toxic exposures after mild traumatic brain injury.

Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.

Chlorpyrifos, permethrin and cyfluthrin effect on cell survival, permeability, and tight junction in an in-vitro model of the human blood-brain barrier (BBB).

The blood-brain barrier (BBB) is a structural and functional interface between the plasma and the human brain. Predictive BBB in-vitro models like immortalized human capillary microvascular endothelial cells (HCMEC/D3) can be used to explore the BBB disruption potential of daily exposed chemicals. The present study was focused on investigating the human BBB permeation potential of one organophosphate pesticide, chlorpyrifos (CPF), and two pyrethroids, permethrin (PMT) and cyfluthrin (CFT). HCMEC/D3 cells were exposed to the chemical and the time-dependent pass across BBB along with permeation coefficient (Papp) was calculated. Transendothelial electrical resistance (TEER) was measured for the cells to check the monolayer formation and later to check the reduction in integrity after chemical exposure. Real time PCR was conducted to investigate the effect of chemicals on the expression BBB´s tight and adherens junction proteins. Calculated Papp value for three chemicals was in the following order: CPF>CFT>PMT, where CPF showed the highest permeation coefficient. TEER calculation showed that the integrity decreased after CPF exposure which was in concordance with Papp value whereas for other chemicals, no change in TEER after exposure was observed. In addition, the transwell study showed a higher efflux ratio (ER) (>2) of CFT indicating that CFT could be a substrate for active transport. For CPF and PMT, ER was less than 2, so no active transport seems to be involved. The evaluation of the mRNA expression analysis revealed a statistically significant decrease in Occludin (OCLN) gene expression for CPF, VE-Cadherin (CDH5) for PMT and Zonula Occludens (ZO1) expression for CFT. Our study showed that CPF has the highest potential for inducing cell death, higher permeation, and capability to induce BBB dysfunction than among the above-mentioned chemicals. Additionally, the results of the permeation study could be useful to build a human PBPK model using in vitro-to-in vivo extrapolation approach.

Hazard Assessment of the Effects of Acute and Chronic Exposure to Permethrin, Copper Hydroxide, Acephate, and Validamycin Nanopesticides on the Physiology of Drosophila: Novel Insights into the Cellular Internalization and Biological Effects.

New insights into the interactions between nanopesticides and edible plants are required in order to elucidate their impacts on human health and agriculture. Nanopesticides include formulations consisting of organic/inorganic nanoparticles. Drosophila melanogaster has become a powerful model in genetic research thanks to its genetic similarity to mammals. This project mainly aimed to generate new evidence for the toxic/genotoxic properties of different nanopesticides (a nanoemulsion (permethrin nanopesticides, 20 ± 5 nm), an inorganic nanoparticle as an active ingredient (copper(II) hydroxide [Cu(OH)2] nanopesticides, 15 ± 6 nm), a polymer-based nanopesticide (acephate nanopesticides, 55 ± 25 nm), and an inorganic nanoparticle associated with an organic active ingredient (validamycin nanopesticides, 1177 ± 220 nm)) and their microparticulate forms (i.e., permethrin, copper(II) sulfate pentahydrate (CuSO4·5H2O), acephate, and validamycin) widely used against agricultural pests, while also showing the merits of using Drosophila-a non-target in vivo eukaryotic model organism-in nanogenotoxicology studies. Significant biological effects were noted at the highest doses of permethrin (0.06 and 0.1 mM), permethrin nanopesticides (1 and 2.5 mM), CuSO4·5H2O (1 and 5 mM), acephate and acephate nanopesticides (1 and 5 mM, respectively), and validamycin and validamycin nanopesticides (1 and 2.5 mM, respectively). The results demonstrating the toxic/genotoxic potential of these nanopesticides through their impact on cellular internalization and gene expression represent significant contributions to future nanogenotoxicology studies.

Long-term low-dose exposure of permethrin induces liver and kidney damage in rats.

BACKGROUND: Permethrin is one of the pyrethroid insecticides, which is widely used in agriculture and public health. Although acute toxicity of the insecticide has been studied, the chronic toxicity upon the long-term exposure has not been clear yet. The purpose of the current study is to investigate the organ toxicities of permethrin following its long-term low-dose exposure. METHODS: Male Wistar rats were daily administrated orally with permethrin (75 mg/kg body weight/day, gavage) for 90 days, and then the samples of biofluids (blood and urine) and organs including liver and kidney were collected. The serum and urine samples were measured by biochemical assay and the tissues of kidney and liver were examined and analyzed by histopathological method. RESULTS: The results showed that no change was found in serum and urine biochemical parameters for the toxicity; however, significant changes including hyperchromatic nuclei swollen in the hepatic parenchymal cells and the swelling proximal tubules in the kidneys were observed in the tissue structures of liver and kidneys in the histopathological sections. CONCLUSION: These results indicate that low-dose long-term exposure of permethrin can cause chronic toxicity with slight liver and kidney damage.

The pyrethroid insecticide permethrin confers hepatotoxicity through DNA damage and mitochondria-associated apoptosis induction in rat: Palliative benefits of Fumaria officinalis.

Permethrin (PER) is a pyrethroid pesticide that is extensively used as an insecticide in world because of its high activity and its low mammalian toxicity. The current study was conducted to investigate the protective action of Fumaria officinalis against PER-induced liver injury in male rats. However, HPLC-DAD showed the richness of 6 components in F. officinalis (F) including quercetin, ferulic acid, and naringenin which were the most abundant. Total polyphenols, total flavonoids, and condensed tannins were studied by phytochemical screening. In vitro, antioxidant properties showed that F. officinalis exhibited the highest DPPH radical, FRAP, and H2 O2 tests and total antioxidant capacity. Wistar rats were divided into four groups: negative control group (C), positive control group (F) (200 mg F. officinalis/kg BW), PER group (34.05 mg permethrin/kg BW), and PER + F group (34.05 mg permethrin/kg BW and 200 mg F. officinalis/kg BW). Oral administration of PER led to promote a decrease of body weight and Ca2+ -ATPases and Mg2+ -ATPases activities and an increase of plasma C-reactive protein level, transaminases, and hepatic ϒ-GT activities as well as hepatic and mitochondrial oxidative stress. An increase in plasma lactate-to pyruvate ratio and a reduction in complexes enzymes I, III, and IV activities were also observed. In addition, histoarchitecture of liver in PER-treated rats showed apoptosis and necrosis as confirmed by DNA fragmentation. F. officinalis significantly exerted hepatoprotective effect by modulating hepatic alteration and mitochondrial dysfunction as well as genotoxicity. This effect could be attributed to phenolics compounds such as polyphenols, condensed tannins, and flavonoids.

Acute toxicity and teratogenicity of carbaryl (carbamates), tebufenpyrad (pyrazoles), cypermethrin and permethrin (pyrethroids) on the European sea bass (Dicentrarchus labrax L, 1758) early life stages.

The toxicity of carbaryl, tebufenpyrad, cypermethrin and permethrin was evaluated in European sea bass Dicentrarchus labrax during the embryonic and larval development using six different concentrations per chemical. The order of the toxicity effectiveness was carbaryl > tebufenpyrad > cypermethrin > permethrin. The larvae were more sensitive to all tested chemicals than embryos. The LC50 of carbaryl, tebufenpyrad, cypermethrin and permethrin was determined as 13.88, 43.96, 92 and 142 ppm and 9.27, 25.67, 48.4 and 72.7 ppm in embryo and larvae, respectively. Furthermore, the tested pesticides exhibited teratogenic effects on D. labrax embryo-larval stages. The observed malformations were coagulation, no spherical egg, unhatched egg, pericardial oedemata, yolk oedemata, lordosis, kyphosis, scoliosis, no eye, cranial deformation and body atrophy. Malformations were induced with 0.5 ppm carbaryl, 10 ppm tebufenpyrad and 50 ppm cypermethrin and permethrin; the highest rates of malformation were noted with 16 ppm carbaryl, 160 ppm tebufenpyrad, 400 ppm cypermethrin and 400 ppm permethrin as 34.5%, 28%, 17.5% and 16%, respectively. A positive correlation between the incidence of malformation and the increase of pesticide concentration was established.

Evaluation of the human hazard of the liver and lung tumors in mice treated with permethrin based on mode of action.

The non-genotoxic synthetic pyrethroid insecticide permethrin produced hepatocellular adenomas and bronchiolo-alveolar adenomas in female CD-1 mice, but not in male CD-1 mice or in female or male Wistar rats. Studies were performed to evaluate possible modes of action (MOAs) for permethrin-induced female CD-1 mouse liver and lung tumor formation. The MOA for liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), increased hepatocellular proliferation, development of altered hepatic foci, and ultimately liver tumors. This MOA is similar to that established for other PPARα activators and is considered to be qualitatively not plausible for humans. The MOA for lung tumor formation by permethrin involves interaction with Club cells, followed by a mitogenic effect resulting in Club cell proliferation, with prolonged administration producing Club cell hyperplasia and subsequently formation of bronchiolo-alveolar adenomas. Although the possibility that permethrin exposure may potentially result in enhancement of Club cell proliferation in humans cannot be completely excluded, there is sufficient information on differences in basic lung anatomy, physiology, metabolism, and biologic behavior of tumors in the general literature to conclude that humans are quantitatively less sensitive to agents that increase Club cell proliferation and lead to tumor formation in mice. The evidence strongly indicates that Club cell mitogens are not likely to lead to increased susceptibility to lung tumor development in humans. Overall, based on MOA evaluation it is concluded that permethrin does not pose a tumorigenic hazard for humans, this conclusion being supported by negative data from permethrin epidemiological studies.

Effects of temperature and salinity on bioconcentration and toxicokinetics of permethrin in pyrethroid-resistant Hyalella azteca.

Recent studies demonstrated pyrethroid resistance associated with voltage-gated sodium channel mutations in populations of the epibenthic amphipod, Hyalella azteca. Resistant populations were able to tolerate and bioconcentrate pyrethroids at concentrations significantly higher than toxic levels for non-resistant populations. In conjunction with elevated bioconcentration potential, environmental alteration particularly as a result of global climate change is anticipated to significantly alter abiotic parameters including temperature and salinity. These changes are expected to influence uptake and biotransformation of contaminants. Thus, the aims of the current study were a) to examine the bioconcentration potential of permethrin in two pyrethroid-resistant clades of H. azteca and b) assess the influence of temperature and salinity changes on toxicokinetic parameters. Two pyrethroid-resistant clades of H. azteca were exposed to 14C-permethrin at three salinities (0.2, 1.0 and 6.0 practical salinity units (PSU)) and temperatures (18, 23 and 28 °C). Tests were conducted for up to 36 h and uptake, elimination and biotransformation rates were calculated. Both populations demonstrated bioconcentration factors (BCFs) between five and seven times greater than published data for non-resistant H. azteca, with significant differences between clades. Calculated BCF values were comparable to field populations of resistant H. azteca, emphasizing the potential for elevated pyrethroid bioconcentration in the natural environment and increased exposure for predators consuming pyrethroid-resistant aquatic invertebrates. Alterations to temperature and salinity had no statistically significant effect on uptake or parent compound half-life in either population, though biotransformation was elevated at higher temperatures in both populations. Salinity had a variable effect between the two populations, with lower BCF values at 1.0 PSU in clade D H. azteca and greater BCFs at 6.0 PSU in clade C H. azteca. This is the first study to demonstrate the potential for future climate scenarios to influence toxicokinetics in pyrethroid-resistant aquatic organisms.