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Neurotoxicology May 2024Exposure to pesticides, such as carbamates, organophosphates, organochlorines and pyrethroids, has been linked to various health problems, including neurotoxicity....
Exposure to pesticides, such as carbamates, organophosphates, organochlorines and pyrethroids, has been linked to various health problems, including neurotoxicity. Although most in vivo studies use only male rodents, some studies have shown in vivo sex-specific effects after acute exposure. Since in vivo studies are costly and require a large number of animals, in vitro assays that take sex-specific effects into account are urgently needed. We therefore assessed the acute effects of exposure to different carbamates (methomyl, aldicarb and carbaryl), organophosphates (chlorpyrifos (CPF), chlorpyrifos-oxon (CPO) and 3,5,6-trichloropyridinol), organochlorines (endosulfan, dieldrin and lindane) and pyrethroids (permethrin, alpha-cypermethrin and 3-phenoxy-benzoic acid (3-PBA)) on neuronal network function in sex-separated rat primary cortical cultures using micro-electrode array (MEA) recordings. Our results indicate that exposure to the carbamate carbaryl and the organophosphates CPF and CPO decreased neuronal activity, with CPO being the most potent. Notably, (network) burst patterns differed between CPF and CPO, with CPO inducing fewer, but more intense (network) bursts. Exposure to low micromolar levels of endosulfan induced a hyperexcitation, most likely due to the antagonistic effects on GABA receptors. Interestingly, females were more sensitive to endosulfan than males. Exposure to dieldrin and lindane also increased neuronal activity, albeit less than endosulfan and without sex-specific effects. Exposure to type I pyrethroid permethrin increased neuronal activity, while exposure to type II pyrethroid alpha-cypermethrin strongly decreased neuronal activity. The increase seen after permethrin exposure was more pronounced in males than in females. Together, these results show that acute exposure to different classes of pesticides exerts differential effects on neuronal activity. Moreover, it shows that MEA recordings are suited to detect sex-specific neurotoxic effects in vitro.
Topics: Animals; Insecticides; Neurons; Female; Male; Cerebral Cortex; Rats; Cells, Cultured; Action Potentials; Dose-Response Relationship, Drug; Microelectrodes; Rats, Wistar
PubMed: 38599286
DOI: 10.1016/j.neuro.2024.04.004 -
Ecotoxicology and Environmental Safety Apr 2024Mounting evidence has shown that the gut microbiota plays a key role in human health. The homeostasis of the gut microbiota could be affected by many factors, including...
Mounting evidence has shown that the gut microbiota plays a key role in human health. The homeostasis of the gut microbiota could be affected by many factors, including environmental chemicals. Aldicarb is a carbamate insecticide used to control a variety of insects and nematode pests in agriculture. Aldicarb is highly toxic and its wide existence has become a global public health concern. In our previous study, we have demonstrated that aldicarb disturbed the gut microbial community structure and composition. However, the impacts of aldicarb on gut microbiota-derived metabolites, bile acids, remain elusive. In present study, we performed targeted metabolomics analysis to explore the effects of aldicarb exposure on bile acids, as well as steroid hormones and oxylipins in the serum, feces and liver of C57BL/6 J mice. Our results showed that aldicarb exposure disturbed the level of various bile acids, steroid hormones and oxylipins in the serum and feces of C57BL/6 J mice. In the liver, the level of cortisol was decreased, meanwhile 15,16-dihydroxyoctadeca-9,12-dienoic acid was increased in aldicarb-treated mice. Metagenomic sequencing analysis showed that the relative abundance of a bile salt hydrolase, choloylglycine hydrolase (EC:3.5.1.24) and a sulfatase enzyme involved in steroid hormone metabolism, arylsulfatase, was significantly increased by aldicarb exposure. Furthermore, correlations were found between gut microbiota and various serum metabolites. The results from this study are helpful to improve the understanding of the impact of carbamate insecticides on host and microbial metabolism.
Topics: Humans; Mice; Animals; Aldicarb; Bile Acids and Salts; Oxylipins; Mice, Inbred C57BL; Insecticides; Hormones; Homeostasis
PubMed: 38564866
DOI: 10.1016/j.ecoenv.2024.116285 -
Frontiers in Bioengineering and... 2024The function of a specific tissue and its biomechanics are interdependent, with pathologies or ageing often being intertwined with structural decline. The biomechanics...
The function of a specific tissue and its biomechanics are interdependent, with pathologies or ageing often being intertwined with structural decline. The biomechanics of , a model organism widely used in pharmacological and ageing research, has been established as biomarker for healthy ageing. However, the properties of the constituent tissues, and their contribution to the overall mechanical characteristics of the organism, remain relatively unknown. In this study we investigated the biomechanics of healthy cuticle, muscle tissue, and pseudocoelom using a combination of indentation experiments and modelling. We performed stiffness measurements using an atomic force microscope. To approximate the nematode's cylindrical body we used a novel three-compartment nonlinear finite element model, enabling us to analyse of how changes in the elasticity of individual compartments affect the bulk stiffness. We then fine-tuned the parameters of the model to match the simulation force-indentation output to the experimental data. To test the finite element model, we modified distinct compartments experimentally. Our results, in agreement with previous studies, suggest that hyperosmotic shock reduces stiffness by decreasing the internal pressure. Unexpectedly, treatment with the neuromuscular agent aldicarb, traditionally associated with muscle contraction, reduced stiffness by decreasing the internal pressure. Furthermore, our finite element model can offer insights into how drugs, mutations, or processes such as ageing target individual tissues.
PubMed: 38558792
DOI: 10.3389/fbioe.2024.1335788 -
Journal of Nematology Feb 2023Reniform nematode () is a major pest of sweetpotato in many production regions in Southern United States. Applying soil fumigants and non-fumigant nematicides are the...
Reniform nematode () is a major pest of sweetpotato in many production regions in Southern United States. Applying soil fumigants and non-fumigant nematicides are the primary management strategies available to growers. This study compared the relative efficacy of nematicides (1,3-dichloropropene, fluopyram, oxamyl, fluazaindolizine, aldicarb, Majestene, and fluensulfone) for management of reniform nematode on sweetpotato. Fumigating soil with 1,3-dichloropropene consistently reduced soil population densities of reniform nematode at the time of planting in both trial years (31 - 36% reduction relative to the untreated control); however, the duration of suppression varied greatly by growing season. A similar trend was observed with fluopyram (56 - 67% reduction) and aldicarb (63 - 65% reduction), which provided season-long suppression of reniform nematode population development in 2021 but had no impact in 2022. In 2021, nematicide application had no impact on yield; however, in 2022, oxamyl and aldicarb increased the yield of U.S.#1 grade sweetpotato. Overall, soil fumigation with 1,3-dichloropropene and in-furrow application of fluopyram and aldicarb provided the most consistent suppression of reniform nematode on sweetpotato.
PubMed: 38283661
DOI: 10.2478/jofnem-2023-0061 -
Aquatic Toxicology (Amsterdam,... Feb 2024Neurotoxic compounds can interfere with active gill ventilation in fish, which might lead to premature death in adult fish, but not in skin-breathing embryos of...
Neurotoxic compounds can interfere with active gill ventilation in fish, which might lead to premature death in adult fish, but not in skin-breathing embryos of zebrafish, since these exclusively rely on passive diffusion across the skin. Regarding lethality, this respiratory failure syndrome (RFS) has been discussed as one of the main reasons for the higher sensitivity of adult fish in the acute fish toxicity test (AFT), if compared to embryos in the fish embryo toxicity test (FET). To further elucidate the relationship between the onset of gill respiration and death by a neurotoxic mode of action, a comparative study into oxygen consumption (MO), breathing frequency (f) and amplitude (f) was performed with 4 d old skin-breathing and 12 d old early gill-breathing zebrafish. Neurotoxic model substances with an LC FET/AFT ratio of > 10 were used: chlorpyrifos, permethrin, aldicarb, ziram, and fluoxetine. Exposure to hypoxia served as a positive control, whereas aniline was tested as an example of a narcotic substance interfering non-specifically with gill membranes. In 12 d old larvae, all substances caused an increase in MO, f and partly f, whereas effects were minor in 4 d old embryos. An increase of f in 4 d old embryos following exposure to chlorpyrifos, aldicarb and hypoxia could not be correlated with an increased MO and might be attributed either to (1) to the successfully postponed decrease of arterial partial pressure of oxygen (PO) through support of skin respiration by increased f, (2) to an unspecific stimulation of the sphincter muscles at the base of the gill filaments, or (3) to the establishment of oxygen sensing for later stages. In gill-breathing 12 d old zebrafish, a concentration-dependent increase of f was detected for aniline and chlorpyrifos, whereas for aldicarb, fluoxetine and permethrin, a decline of f at higher substance concentrations was measured, most likely due to the onset of paralysis and/or fatigue of the gill filament sphincter muscles. Since alterations of f serve to postpone the decrease in arterial PO and MO increased with decreasing f, the respiratory failure syndrome could clearly be demonstrated in 12 d old zebrafish larvae. Passive respiration across the skin in zebrafish embryos could thus be confirmed as a probable reason for the lower sensitivity of early life-stages to neurotoxicants. Integration of respiratory markers into existing testing protocols with non-protected developmental stages such as embryos might help to not underestimate the toxicity of early life-stages of fish.
Topics: Animals; Zebrafish; Pesticides; Aldicarb; Chlorpyrifos; Gills; Permethrin; Fluoxetine; Water Pollutants, Chemical; Toxicity Tests, Acute; Respiration; Oxygen; Respiratory Insufficiency; Aniline Compounds; Larva; Embryo, Nonmammalian
PubMed: 38244448
DOI: 10.1016/j.aquatox.2024.106831 -
Se Pu = Chinese Journal of... Sep 2023Carbamates are used in broad-spectrum insecticides and herbicides, and have highly efficient, low-residue, and long-lasting characteristics. However, this type of...
[Determination of 10 carbamate pesticide residues in liquid milk by ultra performance liquid chromatography-tandem mass spectrometry with pass-through solid-phase extraction purification].
Carbamates are used in broad-spectrum insecticides and herbicides, and have highly efficient, low-residue, and long-lasting characteristics. However, this type of pesticide exerts mutagenic, teratogenic, carcinogenic, and other adverse effects, and its frequent use can exceed the recommended scope and limits. Research on the determination of carbamate pesticides mainly focuses on foods of plant origin and pays less attention to foods of animal origin. The methods for carbamate determination described in the current national standards have complicated operating procedures and low efficiency. Therefore, highly efficient and accurate methods for carbamate detection in milk must be established. In this work, a rapid method based on pass-through solid-phase extraction (SPE) purification coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of 10 carbamate pesticides in liquid milk. The pretreatment and instrument methods were systematically optimized. The milk sample was extracted with acetonitrile, and then purified using a Captiva EMR-Lipid filtration kit. The purified extract was separated on an ACQUITY UPLC BEH C column with mobile phase of methanol and 0.1% formic acid aqueous solution in gradient elution. The flow rate was 0.3 mL/min. Column temperature was 35 ℃. Quantitative analysis was performed using the external standard method with matrix matching curves. The 10 carbamate pesticides showed good linear relationships in the mass concentration range of 2-200 μg/L, with correlation coefficients greater than 0.999. The limits of detection (LODs) and quantification (LOQs) for the 10 carbamate pesticides were 0.045-0.23 and 0.15-0.77 μg/kg, respectively. Recovery tests were conducted using the blank-matrix method at three spiked levels of 15, 50, and 100 μg/kg, and good recoveries for the 10 carbamate pesticides were obtained. In particular, the recoveries for the three spiked levels of 15, 50, and 100 μg/kg were 68.7%-93.3% with relative standard deviations (RSDs) of 1.8%-8.0%. The proposed method is efficient, convenient, accurate, and suitable for the rapid detection of the 10 carbamate pesticides in liquid milk. Compared with the conventional NH and ENVI-18 SPE columns used in the national standard determination method, the proposed method demonstrated better purification effects. The recoveries for aldicarb sulfoxide, aldicarb sulfone, methomyl, and carbaryl after purification using the Captiva EMR-Lipid kit increased from 60% to 80%. Thus, the proposed method is suitable for targets with strong polarity and gives measurement results with good repeatability and accuracy.
Topics: Animals; Pesticide Residues; Carbamates; Milk; Chromatography, Liquid; Tandem Mass Spectrometry; Pesticides; Lipids
PubMed: 37712545
DOI: 10.3724/SP.J.1123.2023.03017 -
ACS Omega Aug 2023Pesticides are widely used, resulting in continuing human exposure with potential health impacts. Some exposures related to agricultural works have been associated with...
Research of Pesticide Metabolites in Human Brain Tumor Tissues by Chemometrics-Based Gas Chromatography-Mass Spectrometry Analysis for a Hypothetical Correlation between Pesticide Exposure and Risk Factor of Central Nervous System Tumors.
Pesticides are widely used, resulting in continuing human exposure with potential health impacts. Some exposures related to agricultural works have been associated with neurological disorders. Since the 2000s, the hypothesis of the role of pesticides in the occurrence of central nervous system (CNS) tumors has been better documented in the literature. However, the etiology of childhood brain cancers still remains largely unknown. The major objective of this work was to assess the potential role of pesticide exposure as a risk factor for CNS tumors based on questionnaires and statistical analysis of information collected from patients hospitalized in the Neurosurgery Department of the Habib Bourguiba Hospital Medium in Sfax, Tunisia, during the period from January 1, 2022, to May 31, 2023. It also aimed to develop a simple and rapid analytical method by the gas chromatography-mass spectrometry technique for the research traces of pesticide metabolites in some collected human brain tumor tissues in order to more emphasize our hypothesis for such a correlation between pesticide exposure and brain tumor development. Patients with a history of high-risk exposure were selected to conduct further analysis. Chemometric methods were adapted to discern intrinsic variation between pathological and control groups and ascertain effective separation with the identification of differentially expressed metabolites accountable for such variations. Three samples revealed traces of pesticide metabolites that were mostly detected at an early age. The histopathological diagnosis was medulloblastoma for a 10-year-old child and high-grade gliomas for 27- and 35-year-old adults. The bivariate analyses (odds ratio >1 and value <5%) confirmed the great probability of developing cancer by an exposure case. The Cox proportional hazards model revealed the risk of carcinogenicity beyond the age of 50 as a long-term effect of pesticide toxicity. Our study supports the correlation between pesticide exposure and the risk of development of human brain tumors, suggesting that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased childhood brain tumor risk. This hypothesis was enhanced in identifying traces of metabolites from the carbamate insecticide class known for their neurotoxicity and others from pyridazinone, organochlorines (OCs), triazole fungicide, and N-nitroso compounds known for their carcinogenicity. The 2D-OXYBLOT analysis confirmed the neurotoxicity effect of insecticides to induce oxidative damage in CNS cells. Aldicarb was implicated in brain carcinogenicity confirmed by the identification of oxime metabolites in a stress degradation study. Revealing "aziridine" metabolites from the OC class may better emphasize the theory of detecting traces of pesticide metabolites at an early age. Overall, our findings lead to the recommendation of limiting the residential use of pesticides and the support of public health policies serving this objective that we need to be vigilant in the postmarketing surveillance of human health impacts.
PubMed: 37599976
DOI: 10.1021/acsomega.3c04592 -
Frontiers in Molecular Neuroscience 2023mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders...
mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient's cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the gene, (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of locomotion indicates that mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype-phenotype correlations of -related disorders.
PubMed: 37324589
DOI: 10.3389/fnmol.2023.1170061 -
Brain Sciences Apr 2023Organophosphate (OP) and carbamate pesticides are toxic to pests through targeted inhibition of acetylcholinesterase (AChE). However, OPs and carbamates may be harmful...
Differentiated Neurons Are More Vulnerable to Organophosphate and Carbamate Neurotoxicity than Undifferentiated Neurons Due to the Induction of Redox Stress and Accumulate Oxidatively-Damaged Proteins.
Organophosphate (OP) and carbamate pesticides are toxic to pests through targeted inhibition of acetylcholinesterase (AChE). However, OPs and carbamates may be harmful to non-target species including humans and could induce developmental neurotoxicity if differentiated or differentiating neurons are particularly vulnerable to neurotoxicant exposures. Hence, this study compared the neurotoxicity of OPs, chlorpyrifos-oxon (CPO), and azamethiphos (AZO) and the carbamate pesticide, aldicarb, to undifferentiated versus differentiated SH-SY5Y neuroblastoma cells. OP and carbamate concentration-response curves for cell viability were undertaken using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays and cellular bioenergetic capacity assessed via quantitation of cellular ATP levels. Concentration-response curves for inhibition of cellular AChE activity were also generated and the production of reactive oxygen species (ROS) was monitored using a 2',7'-dichlorofluorescein diacetate (DCFDA) assay. The OPs and aldicarb reduced cell viability, cellular ATP levels, and neurite outgrowth in a concentration-dependent fashion, from a threshold concentration of ≥10 µM. Neurotoxic potency was in the order AZO > CPO > aldicarb for undifferentiated cells but CPO > AZO > aldicarb for differentiated cells and this toxic potency of CPO reflected its more extensive induction of reactive oxygen species (ROS) and generation of carbonylated proteins that were characterized by western blotting. Hence, the relative neurotoxicity of the OPs and aldicarb in part reflects non-cholinergic mechanisms that are likely to contribute to developmental neurotoxicity.
PubMed: 37239200
DOI: 10.3390/brainsci13050728