Common Mode Of Action Research Articles

Toxicological evaluation of multi-class pesticide residues in vegetables and associated human health risk study for adults and children

ABSTRACTThis article describes, for the first time in 10 years, the toxicological evaluation of pesticide residues in highly consumed vegetables (35 commodities) and health risk studies. Among 1075 vegetable samples consisting mainly of tuber, root, fruiting, and Brassica, 20% of samples contained 38 pesticides in the range of 0.005–18.7 mg/kg and 1% > maximum residue limits (MRLs). Organophosphates and chloronitrile were most frequently found (20%) in the pesticide class. The highest concentration of 18.7 mg/kg was noted for dichlofluanid. Fruiting vegetables (8%), especially tomatoes (5%), were the most contaminated, while multi-residues were determined in 5% of the samples. Risk assessment was performed by analytical results and consumption on the 97.5 percentile expressed as hazard index (HI) and hazard quotient (HQ). The highest chronic HI was calculated for diazinon in lettuce (32% Acceptable Daily Intake (ADI) adults and 36% children) and for forbidden dieldrin in carrots (26%, 62% ADI). The highest acute HI was estimated for dichlofluanid in lettuce (69% Acute Reference Dose (ARfD)) for adults, whereas for children it was above the acceptance values of ARfD (168%). Organophosphate insecticides with common mode of action showed the greatest HQ (108% ADI). Vegetables may not be a serious problem for consumers, but investigations on pesticide residues are necessary to ensure food safety and the protection of human health, especially toward children who are more highly exposed to pesticides than adults.

Toxicological studies for adults and children of insecticide residues with common mode of action (MoA) in pome, stone, berries and other small fruit

The presence of pesticide residues in fruit is a serious health concern. This paper for the first time demonstrated the Hazard Index (HI) method to carry out acute, chronic and cumulative health risk assessment to the 14 groups of insecticides for three subpopulations. The challenge of this study was to present results from a long period of research (years 2005–2014) with toxicological aspects, especially in multiresidue samples. Near 1000 fresh pome, stone, berries and small fruit were prepared by two accredited MSPD and QuEChERS methods followed by liquid and gas chromatography analyses with various systems of detection ECD/NPD/MS/MS. Twenty percent of the fruit samples contained 16 insecticide residues in the range of 0.01–0.81mg/kg and 3% over MRL. The class of pesticide with the highest contribution to the ADI was found to be OPPs: dimethoate and diazinon for adults 48% and 66% of the ADI whereas for infants 144% and 294% of the ADI. The highest contributions of the cHQ to common MoA pesticides were AChE inhibitors: 135% for adults and 528% for infants, sodium channel modulators 4.9% and 20%, nicotic acetylocholine receptor <2.9% and <10.6% for adults and infants, respectively. The fruit with the highest contribution to the ADI were found to be apples (316%, 58%), cherries (96%, 37%) and pears (129%, 33%) for infants and adults. The study findings indicated that dietary exposures to insecticide residues in fruit would be unlikely to pose unacceptable health risks for the infants, toddlers and adults.

Comparison among four triazole fungicides on growth and development of sheath blight of rice pathogen Rhizoctonia solani Kühn AG1-1A

The sheath blight of rice pathogen Rhizoctonia solani Kühn AG1-1A has long been known as a major crisis in global rice production. The present study aimed to compare the efficacy of four triazole fungicides at different doses on the growth and development of R. solani Kühn AG1-1A. Obtained results demonstrated inhibitory effects of all four fungicides on mycelial growth, sclerotia formation and biomass production of R. solani Kühn AG1-1A with significant variation among the treatment doses as well as fungicide molecules (p ≤ 0.05). At the respective EC50 doses all four fungicides inhibited cell wall degrading enzymes viz. invertase, cellulase, polygalacturonase and pectin lyase, of the sheath blight pathogen. The extent of inhibition of the enzymes significantly varied among the fungicides. It is important to note that in spite of having common mode of action, all four triazole fungicides demonstrated significant variation in their fungicidal efficacy on R. solani Kühn AG1-1A.

The Natural Product Resveratrol Inhibits Yeast Cell Separation by Extensively Modulating the Transcriptional Landscape and Reprogramming the Intracellular Metabolome.

An increasing number of studies have shown that the promising compound resveratrol treats multiple diseases, such as cancer and aging; however, the resveratrol mode-of-action (MoA) remains largely unknown. Here, by virtue of multiple omics approaches, we adopted fission yeast as a model system with the goal of dissecting the common MoA of the anti-proliferative activity of resveratrol. We found that the anti-proliferative activity of resveratrol is mainly due to its unique role of inhibiting the separation of sister cells, similar phenotype with the C2H2 zinc finger transcription factor Ace2 knock-out strain. Microarray analysis shown that resveratrol has extensive impact on the fission yeast transcription levels. Among the changed gene’s list, 40% of up-regulated genes are Core Environmental Stress Responses genes, and 57% of the down-regulated genes are periodically expressed. Moreover, resveratrol leverages the metabolome, which unbalances the intracellular pool sizes of several classes of amino acids, nucleosides, sugars and lipids, thus reflecting the remodulated metabolic networks. The complexity of the resveratrol MoA displayed in previous reports and our work demonstrates that multiple omics approaches must be applied together to obtain a complete picture of resveratrol’s anti-proliferative function.

Comparative transcriptomic analyses to scrutinize the assumption that genotoxic PAHs exert effects via a common mode of action.

In this study, the accuracy of the assumption that genotoxic, carcinogenic polycyclic aromatic hydrocarbons (PAHs) act via similar mechanisms of action as benzo(a)pyrene (BaP), the reference PAH used in the human health risk assessment of PAH-containing complex mixtures, was investigated. Adult male Muta™Mouse were gavaged for 28 days with seven individual, genotoxic PAHs. Global gene expression profiles in forestomach, liver, and lung (target tissues of exposure) were determined at 3 days post-exposure. The results are compared with our previously published results from mice exposed to BaP via the same exposure regimen. Although all PAHs showed enhanced ethoxyresorufin-O-deethylase activity, DNA adduct formation, and lacZ mutant frequency in the lungs, the unsupervised cluster analysis of differentially expressed genes revealed that the transcriptional changes are both PAH- and tissue-specific, with lung showing the most response. Further bioinformatics-/pathway-based analysis revealed that all PAHs induce expression of genes associated with carcinogenic processes, including DNA damage response, immune/inflammatory response, or cell signaling processes; however, the type of pathways and the magnitude of change varied for each PAH and were not the same as those observed for BaP. Benchmark dose modeling showed transcriptomic data closely reflected the known tumor incidence for the individual PAHs in each tissue. Collectively, the results suggest that the underlying mechanisms of PAH-induced toxicity leading to tumorigenesis are tissue-specific and not the same for all PAHs; based on the tissue type considered, use of BaP as a reference chemical may overestimate or underestimate the carcinogenic potential of PAHs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1595-5) contains supplementary material, which is available to authorized users.

Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action?

This review summarizes evidence that commercially available fluoroquinolones used for the treatment of bacterial infections are active against other non-bacterial infectious agents as well. Any of these fluoroquinolones exerts, in parallel to its antibacterial action, antiviral, antifungal, and antiparasitic actions at clinically achievable concentrations. This broad range of anti-infective activities is due to one common mode of action, i.e., the inhibition of type II topoisomerases or inhibition of viral helicases, thus maintaining the selective toxicity of fluoroquinolones inhibiting microbial topoisomerases at low concentrations but mammalian topoisomerases at much higher concentrations. Evidence suggests that standard doses of the fluoroquinolones studied are clinically effective against viral and parasitic infections, whereas higher doses administered topically were active against Candida spp. causing ophthalmological infections. Well-designed clinical studies should be performed to substantiate these findings.

Cancer imaging in the era of precision treatment: present and future

Cancer imaging in the era of precision treatment: present and future

The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease.

Long non-coding RNAs (lncRNAs) are transcripts with low protein-coding potential that represent a large proportion of the transcriptional output of the cell. Many lncRNAs exhibit features indicative of functionality including tissue-restricted expression, localization to distinct subcellular structures, regulated expression and evolutionary conservation. Some lncRNAs have been shown to associate with chromatin-modifying activities and transcription factors, suggesting that a common mode of action may be to guide protein complexes to target genomic loci. However, the functions (if any) of the vast majority of lncRNA transcripts are currently unknown, and the subject of investigation. Here, we consider the putative role(s) of lncRNAs in neurodevelopment and brain function with an emphasis on the epigenetic regulation of gene expression. Associations of lncRNAs with neurodevelopmental/neuropsychiatric disorders, neurodegeneration and brain cancers are also discussed.

Disulfide Oil Hazard Assessment Using Categorical Analysis and a Mode of Action Determination

Diethyl and diphenyl disulfides, naphtha sweetening (Chemical Abstracts Service [CAS] # 68955-96-4), are primarily composed of low-molecular-weight dialkyl disulfides extracted from C4 to C5 light hydrocarbon streams during the refining of crude oil. The substance, commonly known as disulfide oil (DSO), can be composed of up to 17 different disulfides and trisulfides with monoalkyl chain lengths no greater than C4. The disulfides in DSO constitute a homologous series of chemical constituents that are perfectly suited for a hazard evaluation using a read-across/worst-case approach. The DSO constituents exhibit a common mode of action that is operable at all trophic levels. The observed oxidative stress response is mediated by reactive oxygen species and free radical intermediates generated after disulfide bond cleavage and subsequent redox cycling of the resulting mercaptan. Evidence indicates that the lowest series member, dimethyl disulfide (DMDS), can operate as a worst-case surrogate for other members of the series, since it displays the highest toxicity. Increasing the alkyl chain length or degree of substitution has been shown to serially reduce disulfide toxicity through resonance stabilization of the radical intermediate or steric inhibition of the initial enzymatic step. The following case study examines the mode of action for dialkyl disulfide toxicity and documents the use of read-across information from DMDS to assess the hazards of DSO. The results indicate that DSO possesses high aquatic toxicity, moderate environmental persistence, low to moderate acute toxicity, high repeated dose toxicity, and a low potential for genotoxicity, carcinogenicity, and reproductive/developmental effects.

Abstract C105: Development and utilization of a cell morphology database, MorphoBase, for drug target identification.

Abstract Background: Tumor cells often dynamically and specifically change shape depending on the mode of action of a drug. It prompted us to accumulate information on morphological changes induced by various compounds with known mechanisms and construct a database linking morphology to drug function, termed “MorphoBase,” which may be helpful in the target identification of a drug and the discovery of unique bioactive compounds. Material and Methods: We designed a high-content imaging algorithm to segment the cells and quantify the effects of various authentic compounds on morphological changes in 2 cancer cell lines, srcts-NRK and HeLa cells, against 12 morphological parameters. We also developed a data analysis program that incorporated multivariate statistical tools to analyze the similarities in morphological changes; principal component analysis (PCA) was applied to visualize phenotypic responses, and the similarities in morphological changes were ranked by 2 statistical computations: “Similarity ranking” determined by Euclidean distances and “Probability scores.” Results: A test set of 208 authentic compounds was created and their multiparametric phenotype responses were analyzed. As a result, inhibitors with a common mode of action formed clusters in PCA and were mutually ranked in their top 20 nearest neighbors, suggesting that MorphoBase can be used to successfully profile phenotypes by drug function. The importance of this database was verified by establishing the molecular targets of three antimitotic drugs and a new cytotoxic fungal metabolite pyrrolizilactone. When compared the similarity in induction of each morphologic feature with those in the dataset, their molecular targets were predicted to be tubulin and proteasome, respectively. We thus demonstrated that these compounds actually inhibit plausible targets in vitro and in a cell-based system. Conclusions: As an alternative to current high-content approaches, we developed a phenotype profiling system, based on MorphoBase. Our new system classifies the compounds by mode of action and predicts the molecular target of compounds with unknown mechanisms. This sensitive and convenient profiling tool has the potential to significantly cut the time it takes to establish on- and off-target effects of novel anticancer drugs, and will facilitate the discovery of bioactive compounds with unique mechanisms of action as well. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C105. Citation Format: Yushi Futamura, Makoto Kawatani, Makoto Muroi, Harumi Aono, Hiroyuki Osada. Development and utilization of a cell morphology database, MorphoBase, for drug target identification. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C105.

Metabolomic Profiling of In Vivo Plasma Responses to Dioxin-Associated Dietary Contaminant Exposure in Rats: Implications for Identification of Sources of Animal and Human Exposure

Dioxin contamination of the food chain typically occurs when cocktails of combustion residues or polychlorinated biphenyl (PCB) containing oils become incorporated into animal feed. These highly toxic compounds are bioaccumulative with small amounts posing a major health risk. The ability to identify animal exposure to these compounds prior to their entry into the food chain may be an invaluable tool to safeguard public health. Dioxin-like compounds act by a common mode of action and this suggests that markers or patterns of response may facilitate identification of exposed animals. However, secondary co-contaminating compounds present in typical dioxin sources may affect responses to compounds. This study has investigated for the first time the potential of a metabolomics platform to distinguish between animals exposed to different sources of dioxin contamination through their diet. Sprague-Dawley rats were given feed containing dioxin-like toxins from hospital incinerator soot, a common PCB oil standard and pure 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (normalized at 0.1 μg/kg TEQ) and acquired plasma was subsequently biochemically profiled using ultra high performance liquid chromatography (UPLC) quadropole time-of-flight-mass spectrometry (QTof-MS). An OPLS-DA model was generated from acquired metabolite fingerprints and validated which allowed classification of plasma from individual animals into the four dietary exposure study groups with a level of accuracy of 97-100%. A set of 24 ions of importance to the prediction model, and which had levels significantly altered between feeding groups, were positively identified as deriving from eight identifiable metabolites including lysophosphatidylcholine (16:0) and tyrosine. This study demonstrates the enormous potential of metabolomic-based profiling to provide a powerful and reliable tool for the detection of dioxin exposure in food-producing animals.

Effects of mixtures of azole fungicides in postimplantation rat whole-embryo cultures

The effect of mixtures of azole fungicides on development of postimplantation rat whole-embryos cultured in vitro has been tested. On the basis of bench mark dose (BMD) modeling of the in vitro effect in rat embryo, the potency of 7 azoles was determined and compared. Then, relative potency factors have been derived based on either the NOAEL or on the BMD curve. Alternatively, each compound was used as index compound (IC), and IC-equivalent concentrations have been calculated for each mixture. Expected effects of such IC-equivalent concentrations of the mixture were derived from the appropriate BMD curve. Test mixture includes the agrochemicals triadimefon and imazalil (MIX2) or triadimefon, imazalil, and the clinically used fluconazole (MIX3) at their previously determined no-effect concentration, corresponding to approximately a benchmark response of 5-10 %. Subsequently, we tested the effect of a mixture of the agrochemicals triadimefon, imazalil, triadimenol, cyproconazole, tebuconazole, and flusilazole (MIX6) at concentration levels derived from their established human acceptable daily intake. MIX6 was also added with fluconazole at concentration levels indicated as the minimum therapeutically effective plasmatic concentration (MIX7A) or ten times this level (MIX7B). Generally, the experimental response was higher than the estimated one, by a factor of 2-6. Our data suggest that it is in principle correct to assume that azoles act as teratogens via a common mode of action and therefore should be grouped together for risk assessment. The synergistic effect needs to be confirmed with more combinations of concentrations/compounds in vitro and with specific in vivo experiments.

Cross‐tolerance in amphibians: Wood frog mortality when exposed to three insecticides with a common mode of action

Insecticide tolerance and cross-tolerance in nontarget organisms is often overlooked despite its potential to buffer natural systems from anthropogenic influence. We exposed wood frog tadpoles from 15 populations to three acetylcholine esterase-inhibiting insecticides and found widespread variation in insecticide tolerance and evidence for cross-tolerance to these insecticides. Our results demonstrate that amphibian populations with tolerance to one pesticide may be tolerant to many other pesticides.

A Common Mechanism of Inhibition of the Mycobacterium tuberculosis Mycolic Acid Biosynthetic Pathway by Isoxyl and Thiacetazone

Isoxyl (ISO) and thiacetazone (TAC), two prodrugs once used in the clinical treatment of tuberculosis, have long been thought to abolish Mycobacterium tuberculosis (M. tuberculosis) growth through the inhibition of mycolic acid biosynthesis, but their respective targets in this pathway have remained elusive. Here we show that treating M. tuberculosis with ISO or TAC results in both cases in the accumulation of 3-hydroxy C(18), C(20), and C(22) fatty acids, suggestive of an inhibition of the dehydratase step of the fatty-acid synthase type II elongation cycle. Consistently, overexpression of the essential hadABC genes encoding the (3R)-hydroxyacyl-acyl carrier protein dehydratases resulted in more than a 16- and 80-fold increase in the resistance of M. tuberculosis to ISO and TAC, respectively. A missense mutation in the hadA gene of spontaneous ISO- and TAC-resistant mutants was sufficient to confer upon M. tuberculosis high level resistance to both drugs. Other mutations found in hypersusceptible or resistant M. tuberculosis and Mycobacterium kansasii isolates mapped to hadC. Mutations affecting the non-essential mycolic acid methyltransferases MmaA4 and MmaA2 were also found in M. tuberculosis spontaneous ISO- and TAC-resistant mutants. That MmaA4, at least, participates in the activation of the two prodrugs as proposed earlier is not supported by our biochemical evidence. Instead and in light of the known interactions of both MmaA4 and MmaA2 with HadAB and HadBC, we propose that mutations affecting these enzymes may impact the binding of ISO and TAC to the dehydratases.

Dose response analysis of monophthalates in the murine embryonic stem cell test assessed by cardiomyocyte differentiation and gene expression

The embryonic stem cell test (EST) is based on compound-induced inhibition of cardiomyocyte differentiation of pluripotent stem cells. We examined the use of transcriptomics to assess concentration–effect relationships and performed potency ranking within a chemical class. Three embryotoxic phthalate monoesters, monobutyl phthalate (MBuP), monobenzyl phthalate (MBzP) and mono-(2-ethylhexyl) phthalate (MEHP) and the non-embryotoxic monomethyl phthalate (MMP) were studied for their effects on gene expression. Effects on gene expression were observed at concentrations that did not inhibit cardiomyocyte differentiation or induce cytotoxicity. The embryotoxic phthalate monoesters altered the expression of 668 commonly expressed genes in a concentration-dependent fashion. The same potency ranking was observed for morphology and gene expression (MEHP>MBzP>MBuP>MMP). These results indicate that integrating transcriptomics provides a sensitive method to measure the dose-dependent effects of phthalate monoester exposure and enables potency ranking based on a common mode of action within a class of compounds. Transcriptomic approaches may improve the applicability of the EST, in terms of sensitivity and specificity.

Single Versus Combined Lethal Effects of Three Agricultural Insecticides on Larvae of the Freshwater Insect Chironomus dilutus

Pesticides are currently regulated individually but are present in aquatic systems as mixtures of toxicants. In this study, the lethal effects of three agricultural insecticides--chlorpyrifos, imidacloprid and dimethoate--on Chironomus dilutus larvae were examined. Ninety-six-hour static bioassays were performed using single, binary, and ternary toxicant mixtures. The effects of the binary mixtures were investigated using the MIXTOX model to determine if the mixtures behaved additively, synergistically, or antagonistically. Dimethoate was much less toxic than chlorpyrifos or imidacloprid. Chlorpyrifos and dimethoate were not additive in mixture despite their common mode of action (MOA) and resulted in opposing effects (synergism and antagonism, respectively) when combined with imidacloprid. Synergism was observed in the ternary mixture. These results suggest that current mixture models based on MOA alone may not always be adequate in describing mixture effects, as in the current situation of mixtures with relatively few components. Other factors, such as water solubility, secondary MOA, and mechanisms of toxicity, should also be considered in future investigations of multichemical-mixture effects.

Environmental contaminants and food safety

Food safety is threatened by numerous contaminants, which can originate from environmental pollution, such as toxic metals and organic halogenated compounds; chemicals used in the production of food, such as pesticides and veterinary drugs; contaminants formed during food production and cooking; contaminants arising from food packaging, or natural toxins in food. Consumers’ perceptions of food-related risks have recently been investigated in the 2010 Eurobarometer. The highest concern was reported for pesticides in fruit, vegetables and cereals, with 72% of the respondents being very or fairly worried. Somewhat fewer people were worried about residues like antibiotics and hormones in meat (70%), pollutants like mercury and dioxins (69%), food poisoning from bacteria (62%) or putting on weight (47%). Adverse effects of environmental contaminants may be displayed as developmental toxicity and endocrine disruption, with fetuses and children being vulnerable target groups. One contaminant, which has attracted much attention, is bisphenol A (BPA) and there is a scientific controversy about the low-dose health risks of BPA. BPA is used in the production of polycarbonate plastics and epoxy resins. Human exposure is mainly from packaged food and beverages. BPA binds to estrogen receptors and also acts through other mechanisms on endocrine function. We have investigated effects of BPA on steroidogenic pathways in the human adrenocortical cell line H295R. Secretion of steroidogenic hormones and intermediates were affected at non-toxic levels of BPA. The effects were mediated by inhibition of CYP17 and CYP21 and expressions of steroidogenic genes were downregulated. This may be an additional mechanism behind the endocrine disruptive effects of BPA. One of the greatest challenges in toxicology today is in predicting the risks associated with chemical mixtures. The exposure to contaminants via the diet occurs as a mixture rather than as individual compounds. Thus, food safety is to a high extent dependant on possibilities to predict risks from mixtures. The two models most frequently used are concentration addition and independent action. The main difference between the two models is the assumption of mode of action of the chemicals in the mixture. In concentration addition it is assumed that the chemicals work through a common mode of action and can be regarded as dilutions of each other. In independent action it is assumed that the chemicals act independently via different mode of actions and the mixture effect is predicted by the probabilities of response of the individual chemicals. We have investigated mixture effects of food-related chemicals on secretion of steroids in the human adrenocortical cell line. The results have been compared to the predicted effects from the two prediction models. In general the chemicals acted in an additive manner on secretion of hormones, which could be predicted by both models.

Gene Expression Modifications by Temperature-Toxicants Interactions in Caenorhabditis elegans

Although organophosphorus pesticides (OP) share a common mode of action, there is increased awareness that they elicit a diverse range of gene expression responses. As yet however, there is no clear understanding of these responses and how they interact with ambient environmental conditions. In the present study, we investigated genome-wide gene expression profiles in the nematode Caenorhabditis elegans exposed to two OP, chlorpyrifos and diazinon, in single and combined treatments at different temperatures. Our results show that chlorpyrifos and diazinon induced expression of different genes and that temperature affected the response of detoxification genes to the pesticides. The analysis of transcriptional responses to a combination of chlorpyrifos and diazinon shows interactions between toxicants that affect gene expression. Furthermore, our combined analysis of the transcriptional responses to OP at different temperatures suggests that the combination of OP and high temperatures affect detoxification genes and modified the toxic levels of the pesticides.

Testing the Dose Addition Hypothesis: The Impact of Pyrethroid Insecticide Mixtures on Neurons

Vol. 119, No. 9 News | Science SelectionsOpen AccessTesting the Dose Addition Hypothesis: The Impact of Pyrethroid Insecticide Mixtures on Neuronsis accompanied byAdditivity of Pyrethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture Kris S. Freeman Kris S. Freeman Search for more papers by this author Published:1 September 2011https://doi.org/10.1289/ehp.119-a399aAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Pyrethroid insecticides are used extensively in agriculture and in homes to control fleas, cockroaches, bedbugs, and other insects. In a new in vitro study researchers tested the hypothesis that mixtures of pyrethroids have a dose-additive effect—that is, that pyrethroids as a chemical group produce toxicity in mammals via a common mode of action and that the combined toxicity of a pyrethroid mixture reflects the sum of its constituents’ toxicities [EHP 119(9):1239–1246; Cao et al.]. Using increased sodium ion influx as a specific functional measure of toxicity, the researchers found that effects of a mixture of commonly used pyrethroids were consistent with a dose-additive effect on mammalian neurons.Pyrethroids act on the nervous system by disrupting the normal function of voltage-gated sodium channels (VGSCs), which control the influx of sodium ions into neurons to transmit nerve signals. When VGSCs open, the influx of sodium generates the nerve signal; when they close, the electrical signal halts abruptly. Pyrethroids bind to VGSCs and delay their closing, which causes repetitive nerve stimulation that can lead to muscle tremors as well as interfere with the ability of the channels to respond to stimulation.Previous research demonstrated that a mixture of 11 pyrethroids had a dose-additive effect on the rat nervous system, decreasing the animals’ motor activity at doses below the threshold dose of each constituent compound. The authors of the current study exposed neurons cultured from the cerebral cortices of embryonic mice to the same 11 pyrethroids, then examined how VGSCs responded. To measure sodium influx without disrupting cell function, neurons were treated with a sodium-sensitive dye that fluoresced when VGSCs were open.Seven of the pyrethroids tested increased sodium influx in a dose-dependent manner (from highest to lowest potency: deltamethrin, S-bioallethrin, β-cyfluthrin, λ-cyhalothrin, esfenvalerate, telfluthrin, fenpropathrin). Cypermethrin and bifenthrin had only a marginal effect on sodium influx, whereas permethrin and resmethrin had no effect. Despite these variations in activity, the results when neurons were exposed to all 11 compounds together were consistent with a cumulative, dose-additive effect on neuronal sodium influx.People are commonly exposed to low doses of pyrethroid mixtures, which tend to persist as residues on treated surfaces and in household dust. Currently the U.S. Environmental Protection Agency is determining whether a cumulative dose-additive model is appropriate to evaluate potential human health effects of pyrethroid mixtures. This model shows that simultaneous exposure to multiple compounds will produce an effect that is consistent with additivity at the VGSC molecular target.FiguresReferencesRelatedDetailsRelated articlesAdditivity of Pyrethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture10 June 2011Environmental Health Perspectives Vol. 119, No. 9 September 2011Metrics About Article Metrics Publication History Originally published1 September 2011Published in print1 September 2011 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Transcutaneous Vagus Nerve Stimulation

Invasive vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. Besides its recognised clinical efficacy, there are major drawbacks, such as invasiveness and a great many side effects. Therefore there is a medical demand for transcutaneous VNS (t-VNS®), which combines selective, non-invasive access to vagus nerve afferents with a low risk profile. Both treatments excite thick myelinated fibres of vagus nerve branches that project to the nucleus of the solitary tract in the brainstem. Preclinical data emphasise the equivalent anticonvulsive effects of both methods. Based upon the common mode of action and the first clinical data, the t-VNS device received Conformité Européenne (CE) approval. Besides the approved intended use for drug-resistant epilepsy and depression, a future clinical trial will address the efficacy of t-VNS in chronic pain.