Allethrin Promotes Apoptosis and Autophagy Associated with the Oxidative Stress-Related PI3K/AKT/mTOR Signaling Pathway in Developing Rat Ovaries.

The increased concern regarding the reduction in female fertility and the impressive numbers of women undergoing fertility treatment support the existence of environmental factors beyond inappropriate programming of developing ovaries. Among these factors are pyrethroids, which are currently some of the most commonly used pesticides worldwide. The present study was performed to investigate the developmental effects of the pyrethroid-based insecticide allethrin on ovarian function in rat offspring in adulthood. We mainly focused on the roles of oxidative stress, apoptosis, autophagy and the related pathways in ovarian injury. Thirty-day-old Wistar albino female rats were intragastrically administered 0 (control), 34.2 or 68.5 mg/kg body weight allethrin after breeding from Day 6 of pregnancy until delivery. We found that allethrin-induced ovarian histopathological damage was accompanied by elevations in oxidative stress and apoptosis. Interestingly, the number of autophagosomes in allethrin-treated ovaries was higher, and this increase was correlated with the upregulated expression of genes and proteins related to the autophagic marker LC-3. Furthermore, allethrin downregulated the expression of PI3K, AKT and mTOR in allethrin-treated ovaries compared with control ovaries. Taken together, the findings of this study suggest that exposure to the pyrethroid-based insecticide allethrin adversely affects both the follicle structure and function in rat offspring during adulthood. Specifically, allethrin can induce excessive oxidative stress and defective autophagy-related apoptosis, probably through inactivation of the PI3K/AKT/mTOR signaling pathway, and these effects may contribute to ovarian dysfunction and impaired fertility in female offspring.

Allethrin-Based Mosquito Control Device Causing Knockdown, Morbidity, and Mortality in Four Species of Field-Caught Mosquitoes (Diptera: Culicidae).

A mosquito control device marketed for spatial repellency, the ThermaCELL Mosquito Repellent Appliance, was evaluated in semifield trials against multiple field-caught species of mosquito. Using paper and mesh cages, mosquito test groups of at least 30 mosquitoes were suspended in a 2,337 cubic foot outdoor space while two ThermaCELL repellent devices were active. After 30 min of treatment, cages were moved to the laboratory to observe knockdown, morbidity, and mortality for 24 h. Species tested included Aedes atlanticus Dyar and Knab (98% average mortality), Psorophora ferox Humboldt (97% average mortality), Psorophora columbiae Dyar and Knab (96% average mortality), and Aedes taeniorhynchus Wiedemann (84% average mortality). The repellent devices showed effectiveness with high knockdown and mortality across all species tested. Mosquito control devices like the ThermaCELL Mosquito Repellent Appliance may have further practical applications to help combat viral exposures by limiting host mosquitoes. Such devices may provide a functional alternative to DEET dependence in the current state of mosquito management.

Protective Effects of Coenzyme Q10 on Testicular Histology in Rats Exposed via Chronic Mosquito Coil Smoke Inhalation.

OBJECTIVE: To determine the preventive effect of coenzyme Q10 (CoQ10) on the testicular histology of rats exposed chronically to mosquito coil smoke. STUDY DESIGN: Experimental study. Place and Duration of the Study: Department of Anatomy, Army Medical College/National University of Medical Sciences, Rawalpindi, Pakistan, from January to December 2020. METHODOLOGY: Thirty male Sprague Dawley rats were divided into three groups of 10 rats each. Group A was the healthy control. Group B rats were exposed to allethrin-based mosquito coil smoke for 12 weeks (4 hours/day). Group C rats received coenzyme Q10 (CoQ10, 10mg/kg/day) through oral gavage, in addition to 12 weeks of mosquito coil smoke exposure (4 hours/day). At the end of the study, testicular histology was compared among three groups including the germinal epithelium height, seminiferous tubule diameter, and testicular capsule thickness, while adjusting for the body weight variations among rats. RESULTS: The rats in Group B, exposed only to mosquito coil smoke showed testicular disruption, characterised by dilated seminiferous tubules (p <0.001), reduced germinal epithelial height (p <0.001), and thickened testicular capsule (p <0.007), as compared to the control group rats. However, the germinal epithelium height (p = 0.73) and testicular capsule thickness (p = 0.31) of rats receiving CoQ10 in addition to mosquito coil smoke inhalation were not significantly different from the control group. CONCLUSION: Prolonged inhalation of allethrin-based mosquito coil smoke can cause testicular disruption among rats. The oral CoQ10 administration can effectively prevent the histomorphological adverse effects on the testis among rats exposed to mosquito coil smoke. KEY WORDS: Allethrin, Coenzyme Q10, Germinal epithelium, Mosquito coil, Seminiferous tubules, Testicular capsule.

The Efficacy of a Pyrethroid-impregnated Mattress Liner on Multiple International Strains of Cimex lectularius (Hemiptera: Cimicidae) and Cimex hemipterus (Hemiptera: Cimicidae).

Modern bed bugs are resistant to multiple insecticide classes, particularly the pyrethroids. The efficacy of pyrethroid-impregnated mattress liners marketed for bed bug management has been variable. This study evaluated the efficacy of a permethrin-impregnated mattress liner, ActiveGuard, against 24 bed bug strains, consisting of both Cimex hemipterus (F.) and Cimex lectularius L. A 'mat assay', employing an allethrin-impregnated mat, was used to establish the pyrethroid resistance profile of all strains. Three experiments were conducted to evaluate the effect of ActiveGuard exposure on bed bug knockdown: 1) exposing the bed bugs continuously on the liner for up to 24 d, 2) holding the bed bugs on the liner for either 4 or 6 h, and 3) placing a noninsecticide treated fabric above the liner with the bed bugs held continuously on top. Our results indicated that all modern strains (collected within the last 15 years during the current resurgence) were pyrethroid-resistant, although the magnitude of resistance was highly variable between strains. In the continuous exposure study, an incomplete knockdown was recorded for most modern bed bug strains, with some having no knockdown even up to 7 d of constant exposure. In the 4 or 6 h exposure study, the level of knockdown was reduced even further, and very few bed bugs were knocked down in the double fabric study. The results of this study indicate that pyrethroid-impregnated mattress liners are not likely to be effective in the management of most modern bed bug infestations involving either C. hemipterus or C. lectularius.

The role of pyrethroid derivatives in autophagy and apoptosis crosstalk signaling and potential risk for malignancies.

Pyrethroids and its derivatives widespread and uncontrolled continuous use has influenced multiple deleterious effects resulting in as a potential risk factor causing damage to the organ systems. Allethrin and prallethrin are extensively used yet their influences on human primary cells are very limited or under reported. The potential mechanisms by which allethrin and prallethrin modulates human primary cells, especially the molecular mechanisms or interconnectivity of autophagy-apoptosis, their clinical relevance in human subjects or patients are not well defined. In this current study, we've furnished the evidence that both allethrin and prallethrin user samples significantly induced Ccl2 mRNA expression, increased amount of reactive oxygen intermediate, inhibited membrane bound enzymes and altered membrane fluidity. Pyrethroid derivative users had induced levels of lipid peroxidation and induced binding activities of transcription factors(tfs) like CEBP-ß and NF-AT. Pyrethroid derivatives induced autophagy, elicited intracellular Ca2+ concentration, calcineurin and regulated proapoptotic genes, DAPK1, Bim. Our current study presumably comprises the initial investigation of a very new mechanism of pyrethroid derivatives-moderated programed cell death in various cell sets or types, like human primary cells where-in this is a late event, is documented. Hence, current research-study might be significant in the various pyrethroid derivatives-allied hematological-related cancers and immunosuppressant or auto-immune disorders. In the foremost instance, we present data stating that pyrethroid derivatives induces multiple cell signaling cascades, like CEBP-ß, NF-AT, ERK and MAPK having a role in autophagy thereby; synchronously effectively impact on the apoptosis, therefore causing hematological tumors and toxic or immune related disorders.

Bioallethrin-induced generation of reactive species and oxidative damage in isolated human erythrocytes.

Bioallethrin is an insecticide that is widely used to control mosquitoes, fleas and cockroaches. The widespread use of bioallethrin has resulted in both occupational and non-occupational human exposure. Bioallethrin enters blood, regardless of the route of exposure, where it can interact with erythrocytes. We have studied the effect of bioallethrin on isolated human erythrocytes under in vitro conditions. Erythrocytes were incubated with increasing concentrations of bioallethrin (10-200 µM) for 4 h at 37 °C. Several biochemical parameters were analyzed in bioallethrin treated and untreated (control) cells. Incubation of erythrocytes with bioallethrin increased protein oxidation, lipid peroxidation and depleted sulfhydryl group content. Membrane damage was evident from cell lysis, osmotic fragility, inhibition of bound enzymes and transmembrane electron transport system. Bioallethrin also increased hemoglobin oxidation, heme degradation and the release of free iron moiety. This will decrease the oxygen transporting ability of blood. Bioallethrin treatment altered the specific activities of antioxidant enzymes and diminished the antioxidant power of cells. Scanning electron microscopy showed that bioallethrin treatment also altered erythrocyte mophology. Almost all changes were in a bioallethrin concentration dependent manner. The cytotoxicity of bioallethrin is probably mediated by reactive oxygen and nitrogen species whose formation was significantly enhanced in treated erythrocytes. Thus bioallethrin enhances the generation of reactive species which cause oxidative damage of cell components in human erythrocytes.

Control of mosquito vectors of tropical infectious diseases: (2) pyrethroid susceptibility of Aedes aegypti ( l) collected from different sites in Thailand.

Four strains (SS, BS, A and B) of Aedes aegypti collected from different sites in Bangkok and at different times were examined for their pyrethroid susceptibility. Mosquito coils containing dl, d-T80-allethrin, d, d-T-prallethrin and methoxymethyl-tetrafluorobenzyl tetramethyl-cyclopropanecarboxylate (K-3050) with or without a synergist were tested by the 25 m3 semi-field test method. One strain (SS) was the most susceptible with KT50 values of about < 30 minutes for all mosquito coils, while the other three strains (BS, A and B) were found to be around 10 to 20 times more tolerant to pyrethroids than the SS strain. A similar tendency for the pyrethroid susceptibility of the four strains was obtained with tests by topical application method. In field efficacy tests, mosquito coils with d, d-T-prallethrin 0.20% plus N-(2-ethylhexyl)bicycle-[2,2,1]- hept-5- ene-2,3-dicarboxyimide as a synergist exhibited a repellent effect of about 85%, while those with K-3050 0.10% plus the synergist exhibited a greater repellent effect of about 90%. In contrast, the repellent effect of commercial dl, d-T80-allethrin 0.20% coils was as low as about 50%. The d, d-T-prallethrin and K-3050 coils with the synergist were confirmed to be highly effective in repelling Ae. aegypti.

Vector control in leishmaniasis.

Indoor residual spraying is a simple and cost effective method of controlling endophilic vectors and DDT remains the insecticide of choice for the control of leishmaniasis. However resistance to insecticide is likely to become more widespread in the population especially in those areas in which insecticide has been used for years. In this context use of slow release emulsified suspension (SRES) may be the best substitute. In this review spraying frequencies of DDT and new schedule of spray have been discussed. Role of biological control and environment management in the control of leishmaniasis has been emphasized. Allethrin (coil) 0.1 and 1.6 per cent prallethrin (liquid) have been found to be effective repellents against Phlebotomus argentipes, the vector of Indian kalaazar. Insecticide impregnated bednets is another area which requires further research on priority basis for the control of leishmaniasis. Role of satellite remote sensing for early prediction of disease by identifying the sandflygenic conditions cannot be undermined. In future synthetic pheromons can be exploited in the control of leishmaniasis.

Ultra low volume aerosol application of deltacide (deltamethrin 0.5% w/v, S-bioallethrin 0.71% w/v & piperonyl butoxide 8.9% w/v) against mosquitoes.

BACKGROUND & OBJECTIVE: Insecticide in the form of space spray as an ultra low volume (ULV) aerosol are used during epidemics of vector borne diseases. Deltacide, a formulation comprising of three chemicals viz., deltamethrin 0.5 per cent w/v, S-bio-allethrin 0.71 per cent w/v and piperonyl butoxide 8.9 per cent w/v is suitable for ULV application. As this combination is found to be effective in preventing resistance development tackling the population, which had already developed resistance and cause immediate mortality, its synergistic effect was tested in Peet Grady chamber, against three species of mosquitoes, viz., Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. METHODS: Blood fed females were exposed to ULV application of deltacide in a Peet Grady chamber at four dosages viz., 0.005, 0.01, 0.02 and 0.04 ml/m2 and examined for knockdown activity at 10 min interval for 60 min. Thereafter, the mosquitoes were removed from the chamber and maintained in another room having controlled temperature (28+/-2 degrees C) and humidity (60-75%) and observed for recovery, if any, and the per cent knockdown was calculated. Mortality rate after 24 h of holding period was also determined from moribund and dead adults. RESULTS: Pairwise comparison showed that the effect of deltacide spray varied significantly (P<0.001) among the three species tested. The effectiveness was significantly higher in Ae. aegypti, when compared with that of Cx. quiquefasciatus (P<0.001) and An. stephensi (P<0.05). However, there was no significant difference in the efficacy of deltacide between Cx. quiquefasciatus and An. stephensi. All species of mosquitoes became inactive i.e., knocked down completely within 60 min of exposure at all the dosages tested and mortality observed was 100 per cent after 24 h of exposure. INTERPRETATION & CONCLUSION: Deltacide when tested in the form of ULV cold aerosol, the dosage 0.01 ml/m2 was effective against both Ae. aegypti, and An. stephensi, and 0.02 ml/m2 against Cx. quiquefasciatus, causing 100 per cent mortality. The efficacy of ULV application of deltacide against vector mosquitoes needs to be assessed under field conditions.

Voltage-dependent gating of veratridine-modified Na channels.

Na channels of frog muscle fibers treated with 100 microM veratridine became transiently modified after a train of repetitive depolarizations. They open and close reversibly with a gating process whose midpoint lies 93 mV more negative than the midpoint of normal activation gating and whose time course shows no appreciable delay in the opening or closing kinetics but still requires more than two kinetic states. Like normal activation, the voltage dependence of the modified gating can be shifted by changing the bathing Ca2+ concentration. The instantaneous current-voltage relation of veratridine-modified channels is curved at potentials negative to -90 mV, as if external Ca ions produced a voltage-dependent block but also permeated. Modified channels probably carry less current than normal ones. When the concentration of veratridine is varied between 5 and 100 microM, the initial rate of modification during a pulse train is directly proportional to the concentration, while the rate of recovery from modification after the train is unaffected. These are the properties expected if drug binding and modification of channels can be equated. Hyperpolarizations that close modified channels slow unbinding. Allethrin and DDT also modify channels. They bind and unbind far faster than veratridine does, and their binding requires open channels.

Influence of pyrethroids and piperonyl butoxide on the Ca(2+)-ATPase activity of rat brain synaptosomes and leukocyte membranes.

Pyrethroids are widely used insecticides of low acute toxicity in mammals but the consequences of long-term exposure are of concern. Their insecticidal action is related to neurotoxicity and, in addition, there are indications of mammalian immunotoxicity. In order to clarify structure-activity relationships of the membrane interactions of pyrethroids, the present study compared the influence of selected pyrethroids, i.e. permethrin and the more water soluble esbiol (S-bioallethrin), both type I, and cyfluthrin, type II, on the Ca(2+)-ATPase activity of rat brain synaptosomes and peritoneal leukocyte membranes. The pyrethroids were tested alone as well as mixed with the enhancing substance piperonyl butoxide (PBO) at concentration ratios of 1:5 and 1:10. At the highest concentration tested, permethrin (10 microM) alone inhibited the ATPase activity of leukocyte membranes by 20%, whereas the synaptosomes were affected less. Esbiol and cyfluthrin alone did not affect either membrane preparation significantly, whereas PBO (50 microM) alone caused 10-15% inhibition. Mixtures of either pyrethroid with PBO inhibited the ATPase activity of both types of membranes (up to 40% inhibition) in a synergistic manner, which always tended to be supra-additive. With esbiol a true potentiation took place. The synergistic interaction between pyrethroid and PBO was most apparent with mixtures of a concentration ratio of 1:5. The ATPase activity of leukocyte membranes tended to be more susceptible to inhibition than that of synaptosomes. The results are in accordance with the assumption that the mammalian toxicity of pyrethroids can be ascribed to a general disturbance of cell membrane function in neuronal tissue. The results indicate that it may also be the case in the immune apparatus.

Laboratory evaluation of three commercial coil products for protection efficacy against Anopheles gambiae from southern Ghana: a preliminary study.

Residents in irrigated urban agricultural sites face numerous mosquito problems such as increased mosquito populations and reduced insecticides susceptibility due to the creation of mosquito breeding sites and agricultural use of insecticides and hence require effective protective products against them. In this study, the protection effectiveness of three pyrethroid formulated mosquito coils of Malaysian origin against Anopheles gambiae sensu lato from an irrigated urban agricultural site in Ghana were evaluated for their potential use. Sucrose fed An. gambiae s.l. were exposed to insecticide-containing coils in a 70 cm x 70 cm x 70 cm glass chamber to assess the insecticidal effect of the coils. The 0.005% metofluthrin coil caused the most rapid knockdown of 50% of the test mosquitoes. The mean lethal effect of the coils on An. gambiae s.l. were as follows; 0.005% metofluthrin (86%), 0.3% d-allethrin (74.33%), 0.15% d-trans allethrin (72%) and the 0.25% d-allethrin reference coil (69%). The 0.005% metofluthrin coil achieved the highest insecticidal effect on An. gambiae s.l. compared to the other coils and hence performed better than the others as an anti-mosquito product. All the three test coils were effective against An. gambaie s.l. from the irrigated agricultural site compared to the reference coil.

Identification of putative kdr mutations in the tropical bed bug, Cimex hemipterus (Hemiptera: Cimicidae).

BACKGROUND: Bed bugs [both Cimex hemipterus (F.) and Cimex lectularius L.] are highly resistant to pyrethroids worldwide. An important resistance mechanism known as 'knockdown resistance' (kdr) is caused by genetic point mutations on the voltage-gated sodium channel (VGSC) gene. Previous studies have identified two point mutations (V419L and L925I) on the VGSC gene in C. lectularius that are responsible for kdr-type resistance. However, the kdr mutations in C. hemipterus have not been investigated. RESULTS: Four novel mutations, L899V (leucine to valine), M918I (methionine to isoleucine), D953G (aspartic acid to glycine) and L1014F (leucine to phenylalanine), were identified in the domain II region of the C. hemipterus VGSC gene. This region has been widely investigated for the study of kdr-type resistance to pyrethroids in other insect pests. The V419L and L925I kdr mutations as previously identified in C. lectularius were not detected in C. hemipterus. CONCLUSION: M918I and L1014F are considered to be probable kdr mutations and may play essential roles in kdr-type resistance to pyrethroids in C. hemipterus. Further studies are under way in the authors' laboratory to determine the non-kdr-type resistance mechanisms in C. hemipterus.

Point mutations in domain III of a Drosophila neuronal Na channel confer resistance to allethrin.

Voltage-gated sodium channels are the presumed site of action of pyrethroid insecticides and DDT. We screened several mutant sodium channel Drosophila lines for resistance to type I pyrethroids. In insecticidal bioassays the para(74) and para(DN7) fly lines showed greater than 4-fold resistance to allethrin relative to the allethrin sensitive Canton-S control line. The amino acid substitutions of both mutants are in domain III. The point mutation associated with para(74) lies within the S6 transmembrane region and the amino acid substitution associated with para(DN7) lies within the S4-S5 linker region. These sites are analogous to the mutations in domain II underlying knockdown resistance (kdr) and super-kdr, naturally occurring forms of pyrethroid resistance found in houseflies and other insects. Electrophysiological studies were performed on isolated Drosophila neurons from wild type and para(74) embryos placed in primary culture for three days to two weeks. The mutant para(74) sodium currents were kinetically similar to wild type currents, in activation, inactivation and time to peak. The only observed difference between para(74) and wild-type neurons was in the affinity of the type I pyrethroid, allethrin. Application of 500 nM allethrin caused removal of inactivation and prolonged tail currents in wild type sodium channels but had little or no effect on para(74) mutant sodium channels.

Inhibition of phosphatase 2B prevents expression of hippocampal long-term potentiation.

The induction of long-term potentiation (LTP) in the CA1 region of the hippocampus is mediated by N-methyl-D-aspartate (NMDA) receptor-coupled calcium influx. In addition, calcium/calmodulin (CaM) has been demonstrated to play an essential role in the induction process. In the present study, a possible role of CaM-dependent phosphatase (phosphatase 2B, PP-2B, calcineurin) in the LTP process was examined by intracellular recordings in apical dendrites of CA1 pyramidal cells of adult guinea-pigs. In dendrites in which cypermethrin, a potent and specific inhibitor of PP-2B (IC50 40 pM), was intracellularly applied, tetanization generated only short-term increases (15-30 min) of excitatory responses. In the intracellular presence of allethrin, a weak inhibitor of PP-2B, LTP expression was not affected. These findings demonstrate that activation of PP-2B is a necessary condition for the expression of LTP in CA1 pyramidal cell dendrites.

Neonatal exposure to a type-I pyrethroid (bioallethrin) induces dose-response changes in brain muscarinic receptors and behaviour in neonatal and adult mice.

This study shows that neonatal exposure to the insecticide bioallethrin has a dose-dependent effect on muscarinic cholinergic receptors (MAChR) in the neonatal mouse, leading to permanent changes in MAChR and in spontaneous behaviour in adult mice. Neonatal NMRI mice, given oral doses of either bioallethrin or the vehicle, once daily between the 10th and 16th postnatal day, were killed at the age of 17 days or 1 week after the spontaneous motor behaviour tests at 4 months. The MAChR were assayed in the cerebral cortex by using the antagonist quinuclidinyl benzilate ([3H]QNB) and the agonist carbachol. In the 17-day-old mice bioallethrin exposure elicited a significant dose-dependent increase in the specific [3H]QNB binding. The competition study showed that the proportion of low-affinity binding was significantly increased in the 17-day-old mice compared with controls. In the adult mouse there was a significant dose-dependent decrease in specific [3H]QNB binding. In these adult mice the behavioural variables 'locomotion' and 'total activity' showed significant (P < or = 0.01) dose-dependent increases at all doses up to and including 0.70 mg/kg b.wt.

Differential sensitivity of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels to the insecticide allethrin in rat dorsal root ganglion neurons.

The pyrethroid insecticides are known to modify neuronal sodium channels to cause a prolongation of whole cell current. The sodium channels expressed in the dorsal root ganglion neurons of the rat are of two types, one highly sensitive to tetrodotoxin and the other highly resistant to tetrodotoxin. The pyrethroid allethrin exerted profound effects on tetrodotoxin-resistant sodium channels while causing minimal effects on tetrodotoxin-sensitive sodium channels. Currents derived from tetrodotoxin-resistant sodium channels were greatly prolonged during a step depolarization; the tail currents upon repolarization were also augmented and prolonged. In the tetrodotoxin-sensitive sodium channel currents, these changes caused by allethrin were much smaller or negligible. The activation and inactivation voltages of tetrodotoxin-resistant peak sodium currents were not significantly altered by allethrin. The differential action of allethrin on the two types of sodium channels would be important not only in identifying the target molecular structure but also in interpreting the symptoms of poisoning in mammals.

Time course and temperature dependence of allethrin modulation of sodium channels in rat dorsal root ganglion cells.

Key effects of the pyrethroid insecticide allethrin, delivered to or washed out from cells at 10 or 100 microM in 0.1% DMSO, on neuronal Na(+) channel currents were studied in rat dorsal root ganglion (DRG) cells under whole-cell patch clamp. Tetrodotoxin-resistant (TTX-R) Na(+) channels were more responsive to allethrin than tetrodotoxin-sensitive (TTX-S) Na(+) channels. On application of 10 or 100 microM allethrin to cells with TTX-R Na(+) channels, the Na(+) tail current during repolarization developed a large slowly decaying component within 10 min. This slow tail developed multiphasically, suggesting that allethrin gains access to Na(+) channels by a multiorder process. On washout (with 0.1% DMSO present), the slow tail current disappeared monophasically (exponential tau=188+/-44 s). Development and washout rates did not depend systematically on temperature (12 degrees, 18 degrees, or 27 degrees C), but washout was slowed severely if DMSO was absent. As the duration of a depolarizing pulse was increased (range 0.32-10 ms), the amplitude of the slow component of the succeeding tail conductance first increased then decreased. Tail current amplitude had the same dependence on preceding pulse duration (at 18 degrees ) at 10 or 100 microM, consistent with allethrin modification of Na(+) channels at rest before opening. At 10 microM, slow tail conductance was at maximum 40% of the peak conductance during the previous depolarization, independent of temperature; evidently, the fraction of open modified channels did not change. However, at low temperature, the tail is more prolonged, bringing more Na(+) ions into a cell. In functioning neurons, this Na(+) influx would cause a larger depolarizing afterpotential, a condition favoring the repetitive discharges, which are signatory of pyrethroid intoxication.

Allethrin interactions with the nicotinic acetylcholine receptor channel.

Interactions of the synthetic pyrethroid allethrin with the nicotinic acetylcholine (ACh) receptor/channel were studied in membranes from Torpedo electric organ. Allethrin did not inhibit binding of [3H]ACh to the receptor sites, but inhibited noncompetitively binding of [3H]perhydrohistrionicotoxin ([3H]H12-HTX) to the ionic channel sites in a dose-dependent manner. The inhibition constant (Ki) of [3H]H12-HTX binding in absence of receptor agonist was 30 micro M, while in presence of 100 micro M carbamylcholine it was 4 micro M. This inhibitory effect of allethrin had a negative temperature coefficient. The high affinity binding of allethrin to the channel sites of the nicotinic ACh-receptor may be indicative of a postsynaptic site of action for pyrethroids, in addition to their known action on the sodium channel.

Effects of pyrethroid insecticides on operant responding maintained by food.

The pyrethroids are potent insecticides with low concomitant mammalian lethality when compared with other major insecticides. While high doses can lead to hyperactivity, tremors, convulsion and death, low doses have not been as well studied. Since operant behavior can be a sensitive measure of CNS function, male Holtzman rats were trained on a VR25 schedule maintained by 45 mg food pellets. Rats were injected IP with one of four different technical grade pyrethroids: permethrin, allethrin, deltamethrin and fenvalerate. All agents were effective in reducing operant responding and did so in a dose-dependent manner at levels 10 to 100 times below their LD50 values. Time course studies indicated a relatively short duration of action for the Type I agents of less than 60 min for permethrin and 15 min for allethrin. Type II agents were generally effective for greater than 60 min. Results of these studies indicate that operant responding maintained by food is a sensitive measure of the behaviorally disruptive effects of subconvulsive doses of pyrethroids.