Organophosphate Exposure Research Articles

Multi-omic profiling of Metabolome and Epigenome Signature Related with OP Exposure

TPS 911: Air pollution, epigenetics, biomarkers, Exhibition Hall, Ground floor, August 26, 2019, 3:00 PM - 4:30 PM Background: Organophosphates (OP) are widely used insecticides that have been associated with a wide range of adverse health outcomes. There is great interest in improving the understanding of molecular mechanisms related to chronic OP exposure induced toxicity. We aim to integrate metabolomics and epigenomics to investigate the pathophysiologic response related with OP exposure on system biology level. Methods: In a population-based case control study of Parkinson’s disease (PD), we assessed ambient OP exposure via residential and workplace proximity to commercial applications. We investigated associations between OP exposure and serum metabolome (LC/MS) as well as genome-wide DNA methylation (Illumina 450 k) in 99 blood samples (79 PD patients, 20 controls). Weighted gene coexpression network analysis (WGCNA) was used to identify modules of correlated CpG sites and metabolites. A partial correlation network was constructed from the modules and the relations between the module network and the OP exposure were investigated. Results: Epigenomic modules associated with OP exposure were enriched in pathways related with acetylcholine and other neurotransmitters’ activity. The associations between OP exposure and oxidative stress and inflammation were observed in both metabolomic and epigenomic profiles. The epigenomic and metabolomic modules were interrelated and showed cross-sectional associations with OP exposure. Conclusion: Long-term OP exposure associates with both metabolome and epigenome. By integrating metabolomics and epigenomics, we illustrated that OP exposure could disrupt neurotransmission, and induce oxidative stress and inflammation, which could then increase the risk of adverse health outcomes.

Organophosphate Exposures, Financial Hardship and Child Neurodevelopmental Outcomes in the CHARGE study

OPS 55: Pesticides and neurological outcomes, Room 412, Floor 4, August 26, 2019, 1:30 PM - 3:00 PM In-utero exposure to organophosphate pesticides has been associated with neurodevelopmental delay. This study examined whether maternal report of inability to pay for basic needs (food, housing, medical care and heating) modified the relationship between prenatal pesticide exposure and autism spectrum disorder (ASD). Methods: We studied 488 children with ASD and 329 typically-developing controls aged 2-5 years enrolled between 2003 and 2008 in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation. Diagnoses were confirmed by standardized assessments and information regarding maternal factors was determined from a structured interview with the mother. Residential proximity to agricultural application of organophosphate pesticides, based on California Department of Pesticide Regulation data, was determined by spatial analysis of maternal residence before and during pregnancy. Multiple logistic regression was used to examine the association between exposure during several time points during the pregnancy, and effect modification by the experience of financial hardship. Results: 213 (26%) CHARGE study mothers lived within 1.5 km of agricultural application of organophosphate compounds during their pregnancies. ASD odds were elevated in those exposed to pesticides between the 3 months prior to conception up through delivery (adjusted odds ratio (aOR) 2.44; 95% CI [1.05, 5.63]). Odds for mothers with 2nd trimester organophosphate exposure was higher for women with financial hardship compared to those without, 3.01; 95% CI [1.34, 6.75] vs 1.92; 95% CI [1.35, 2.76], respectively. This disparity was particularly pronounced for chlorpyrifos exposure, where those with financial hardship exhibited odds ratios ranging from 5 to 15 at all pregnancy timepoints. Conclusions: This study identified financial hardship as an amplifier of the association between organophosphate pesticide exposures during pregnancy and offspring ASD. It adds to the existing evidence highlighting the importance of studying the co-exposure of social and environmental factors affecting children at early developmental stages.

Acute encephalopathy followed by delayed myelopathy a rare presentation of chlorpyriphos (organophosphorus) poisoning

Organophosphorus compounds (OPC) are commonly used pesticides and suicidal ingestion is common mode of poisoning. The manifestation of OPC poisoning and its severity depend upon the type, dose and potency of the OPC consumed. Neurological presentations are well defined clinical syndromes consisting of early, intermediate and delayed manifestations (rare), categorized on the basis of time elapsed since OPC exposure. A 21-years-old male presented to us with 100 ml of pesticide consumption (containing chlorpyriphos 50% and cypermethrin 5%) 18 months prior to presentation. Following intake, he developed one episode of seizure followed by altered sensorium for 3 weeks during which he was treated with atropine infusion and supportive management. He was well for the next two months. Subsequently he developed insidious onset and progressive proximal followed by distal weakness leading to pure motor spastic paraparesis without bowel or bladder involvement. He had brisk lower limb reflexes with extensor plantar response. Routine investigations were normal. Electrophysiological studies (nerve conduction studies, electromyography, visual evoked potentials, brainstem auditory evoked potentials and somatosensory evoked potentials[SSEP] in upper limbs) were normal. SSEP of lower limb showed prolonged potentials beyond the popliteal fossa with normal upper limbs. MRI of the spine showed dorsal cord atrophy and MRI brain was normal. This case reports a rare delayed manifestation of organophosphorus poisoning in the form of pure motor spastic paraparesis due to dorsal myelopathy. A possibility of delayed manifestations of toxicity should be considered in individuals presenting with features suggestive of myelopathy and a previous history of organophosphate exposure.

Microbiota and organophosphates

Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. Consumption of these compounds affects several central nervous system functions. Some of the most recognised consequences of organophosphate pesticide exposure in humans include neonatal developmental abnormalities, endocrine disruption, neurodegeneration, neuroinflammation and cancer. In addition, neurobehavioral and emotional deficits following OP exposure have been reported.It would be of great value to discover a therapeutic strategy which produces a protective effect against these neurotoxic compounds. Moreover, a growing body of preclinical data suggests that the microbiota may affect metabolism and neurotoxic outcomes through exposure to OPs.The human gut is colonised by a broad variety of microorganisms. This huge number of bacteria and other microorganisms which survive by colonising the gastrointestinal tract is defined as “gut microbiota”. The gut microbiome plays a profound role in metabolic processing, energy production, immune and cognitive development and homeostasis. The effects are not only localized in the gut, but also influence many other organs, such as the brain through the microbiome-gut-brain axis. Therefore, given the gut microbiota’s key role in host homeostasis, this microbiota may be altered or modified temporarily by factors such as antibiotics, diet and toxins such as pesticides.The aim of this review is to examine scientific articles concerning the impact of microbiota in OP toxicity. Studies focussed on the possible contribution the microbiota has on variable host pharmacokinetic responses such as absorption and biotransformation of xenobiotics will be evaluated. Microbiome manipulation by antibiotic or probiotic administration and faecal transplantation are experimental approaches recently proposed as treatments for several diseases.Finally, microbiota manipulation as a possible therapeutic strategy in order to reduce OP toxicity will be discussed.

Organophosphate pesticide exposure in children in Israel: Dietary associations and implications for risk assessment

BackgroundHuman biomonitoring (HBM) data is increasingly being compared to risk–based screening values to assess human health risk. However, as screening values have not been established for assessing biomarker concentrations of organophosphate (OP) pesticide metabolites, there are few studies using HBM data on urinary OP concentrations to assess human health risk. The purpose of the current study was to measure OP exposure in a sample of children in Israel; to explore associations between dietary patterns and OP exposure; and to assess risk of OP pesticides using urinary metabolite concentrations. MethodsWe recruited 103 children in Israel and collected demographic and dietary data and urinary samples, and measured creatinine and dialkyl phosphate (DAP) concentrations. We compared urinary DAP concentrations to international populations and analysed associations between fruit and vegetable consumption and urinary DAP concentrations. Using urinary DAP concentrations, we calculated estimated daily intakes (EDI) of OP pesticides in each child and compared those to the acceptable daily intake (ADI). ResultsConcentrations of several dialkyl phosphate metabolites (dimethylphosphate (DMP) and dimethylthiophosphate (DMTP)) were higher in our study population of Israeli children (geometric mean concentrations of DMP and DMTP were 6.6 μg/L and 7.6 μg/L, respectively) compared to children in the US, Canada, Spain, and Denmark. We found positive correlations between total fruit consumption and creatinine adjusted log transformed urinary DMP, DMTP, diethylthiophopshate (DETP), total dimethyl (DM) and total DAP concentrations (p < 0.05), positive correlations between cucumber consumption and diethylphosphate (DEP), DETP and diethyl (DE) concentrations (p < 0.05), and positive correlations between apple consumption and DETP concentrations (p = 0.02). Based on urinary DAP concentrations, we found that a portion of the children in our study had EDIs above the ADI, ranging from 2.9% to 79.4% of the children, depending on the active OP ingredient. ConclusionsWe found that Israeli children in our study are widely exposed to OP pesticides; that levels of dimethyl metabolites were high compared to other international populations; and that fruit consumption was associated with higher urinary DAP levels. Using urinary DAP concentration data, we found that a portion of the children in our study may be exposed to OP pesticides at levels above those considered safe.

Organotypic Neurovascular Unit and Electrochemical Platform for Predictive Toxicology

Organophosphates account for about a third (nine million kilograms in 2012) of all pesticides used in the U.S., yet are toxic to humans, with exposure leading to neurodegenerative disorders and death. The ability to identify organophosphate exposure and predict biological responses has been limited—with epidemiological studies being uncontrolled and murine studies being discordant—leaving critical questions unanswered. In my talk, I will present a platform that uses human-derived cells to form a model blood-brain barrier to perform controlled toxicological studies. As a proof-of-concept experiment, environmental exposure was simulated by adding chlorpyrifos (CPF), the most prevalent organophosphate used in the U.S., to the vascular side of this engineered blood-brain barrier unit. Then, chemical perturbations were probed using a combination of electrochemical assays and mass spectrometry. The substantial metabolic disruption induced by this commercial pesticide will be discussed as well as platform advances (microfluidics and sensors) that made the experiments possible. Broadly, this work may lead to early diagnosis of CPF exposure and inform policies around pesticide use.

Ocular surface histopathological insult following sarin and VX exposure and potential treatments in the rat model

Eye exposure to organophosphate (OP) chemical warfare irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. In contrast to the well-documented miotic and ciliary muscle spasm observed following chemical warfare, OP ocular exposure, little is known regarding the ocular surface histopathological insult. The aim of the present study was to determine the degree of the ocular surface insult following sarin or VX ocular exposure and to evaluate potential anti-cholinergic treatments in counteracting this insult.Rats that were whole body exposed to various sarin concentrations (0.049–43 μg/L; 5 min exposure), showed a dose-dependent miotic response and light reflex impairment.Following whole body sarin exposure, a dose dependent ocular surface histopathological insult was developed. A week following exposure to a low concentration of 0.05 μg/L, conjunctival pathology was observed, while corneal insult was noticed only following exposure to a concentration of 0.5 μg/L and above. Both tissues presented poorer outcomes when exposed to higher sarin concentrations. In contrast, eyes topically exposed to 1 μg sarin demonstrated no ocular insult a week following exposure. On the contrary, topical exposure to 1 μg VX resulted in a significant corneal insult. Anticholinergic treatments such as 0.1% atropine or 2% homatropine, given shortly following VX exposure, counteracted this insult.The results of this study show that not only do anti-cholinergic treatments counteract the miotic response, but also prevent the histopathological insult observed when given shortly following OP exposure.

Potential attenuation of early-life overfeeding-induced metabolic dysfunction by chronic maternal acetylcholinesterase inhibitor exposure

Evidence suggests that low concentration perinatal exposure to environmental contaminants, such as organophosphate (OP) is associated with later life insulin resistance and type 2 diabetes. The aim of this work was to investigate whether chronic maternal OP exposure exacerbates metabolic dysfunctions in early-overfed rats. During pregnancy and lactational periods, dams received OP by gavage. To induce neonatal overnutrition at postnatal day 3, pups were standardized to 9 or 3 per nest. At 90-days-old, glucose-insulin homeostasis and insulin release from pancreatic islets were analyzed. While both OP exposure and overfeeding alone did induce diabetogenic phenotypes in adulthood, there was no exacerbation in rats that experienced both. Unexpectedly, the group that experienced both had improved adiposity, metabolic parameters, attenuated insulin release from isolated islets in the presence of glucose and low function of muscarinic acetylcholine receptor M3, as well as an attenuation of beta cell mass hyperplasia. High levels of butyrylcholinesterase and low levels of insulin in milk may contribute to the OP-induced developmental programming. Our study showed that maternal OP exposure may program insulin release as well as endocrine pancreas structure, thus affecting metabolism in adulthood. Our data suggest that while perinatal OP exposure alone increases the risk for later life T2D, it actually reverses many of the programmed metabolic dysfunction that is induced by postnatal overfeeding. These surprising results may suggest that low-dose administration of acetylcholinesterase inhibitors could be of utility in preventing detrimental developmental programming that is caused by early-life overnutrition.

Effect of a 24-week randomized trial of an organic produce intervention on pyrethroid and organophosphate pesticide exposure among pregnant women

BackgroundIntroduction of an organic diet can significantly reduce exposure to some classes of pesticides in children and adults, but no long-term trials have been conducted. ObjectivesTo assess the effect of a long-term (24-week) organic produce intervention on pesticide exposure among pregnant women. MethodsWe recruited 20 women from the Idaho Women, Infants, and Children (WIC) program during their first trimester of pregnancy. Eligible women were nonsmokers aged 18–35 years who reported eating exclusively conventionally grown food. We randomly assigned participants to receive weekly deliveries of either organic or conventional fruits and vegetables throughout their second or third trimesters and collected weekly spot urine samples. Urine samples, which were pooled to represent monthly exposures, were analyzed for biomarkers of organophosphate (OP) and pyrethroid insecticides. ResultsFood diary data demonstrated that 66% of all servings of fruits and vegetables consumed by participants in the “organic produce” group were organic, compared to <3% in the “conventional produce” group. We collected an average of 23 spot samples per participant (461 samples total), which were combined to yield 116 monthly composites. 3-Phenoxybenzoic acid (3-PBA, a non-specific biomarker of several pyrethroids) was detected in 75% of the composite samples, and 3-PBA concentrations were significantly higher in samples collected from women in the conventional produce group compared to the organic produce group (0.95 vs 0.27 μg/L, p = 0.03). Another pyrethroid biomarker, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, was detected more frequently in women in the conventional compared to the organic produce groups (16% vs 4%, p = 0.05). In contrast, we observed no statistically significant differences in detection frequency or concentrations for any of the four biomarkers of OP exposure quantified in this trial. DiscussionTo our knowledge, this is the first long-term organic diet intervention study, and the first to include pregnant women. These results suggest that addition of organic produce to an individual's diet, as compared to conventional produce, significantly reduces exposure to pyrethroid insecticides.

Mitochondria as a target of organophosphate and carbamate pesticides: Revisiting common mechanisms of action with new approach methodologies

Mitochondrial toxicity has been proposed as a potential cause of developmental defects in humans. We evaluated 51 organophosphate and carbamate pesticides using the U.S. EPA ToxCast and Tox21 databases. Only a small number of them bind directly to cholinesterases in the parent form. The hydrophobicity of organophosphate pesticides is correlated significantly to TSPO binding affinity, mitochondrial membrane potential reduction in HepG2 cells, and developmental toxicity in Caenorhabditis elegans and Danio rerio (p < 0.05). Structural analysis suggests that in some cases the Krebs cycle is a potential target of organophosphate and carbamate exposure at early life stages. The results support the hypothesis that mitochondrial effects of some organophosphate pesticides—particularly those that require enzymatic activation to the oxon form—may augment the documented effects of disruption of acetylcholine signaling. This study provides a proof of concept for applying new approach methodologies to interrogate mechanisms of action for cumulative risk assessment.

Oximes as pretreatment before acute exposure to paraoxon.

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01 ) the prophylactic efficacy of five experimental (K-48, K-53, K-74, K-75, K-203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10-methylacridine) and after the FDA-approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon-induced mortality. Best protection was conferred by the experimental oxime K-48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR=0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K-203), 0.21 (K-74), 0.24 (K-75) and 0.26 (pralidoxime), which were significantly more efficacious than 10-methylacridine (RR=0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.

Hearing Loss in Agricultural Workers Exposed to Pesticides and Noise.

Agricultural workers who have concurrent exposure to pesticides and noise are at increased risk of hearing loss. We recruited 163 Thai conventional and 172 organic farmers to answer our questionnaires about personal demographics, agricultural activities, and pesticide and agricultural machinery use. This information was used to calculate the years of conventional (pesticide use) farming and the years of agricultural noise exposure, and to estimate semiquantitative metrics for pesticide exposure (cumulative intensity score-years) and cumulative noise exposure (dB(A)-years) for each conventional farmer. All participants underwent pure tone audiometric testing. The mean hearing threshold in the low-frequency band (0.5-2 kHz) and high-frequency band (3-6 kHz) were used for analysis. Years involved in conventional farming and years using agricultural machinery were associated with an increase in the average hearing threshold for the high-frequency band after controlling for age, ever exposed to industrial noise and cigarette smoking. The highest category of cumulative insecticide exposure (score-years), cumulative organophosphates exposure (score-years) and cumulative noise exposure (dB(A)-years) were also associated with an increased high-frequency band hearing threshold among conventional farmers. Results from the full cohort and the subcohort of conventional farmers support each other and the hypothesis that pesticide and noise have an additive effect on hearing, since no model interactions were significant.

The effect of acute organophosphate intoxication on female rat hippocampus cornu ammonis region pyramidal neuron numbers, biochemistry and morphology

BackgroundThe most commonly used insecticides and pesticides worldwide are organophosphate compounds, chemicals that irreversibly inhibit the cholinesterase enzyme. Acute intoxication with cholinesterase inhibitors is known to cause permanent effects on both the human and rat brains. AimTo investigate the effect of acute organophosphate intoxication on hippocampus morphology, biochemistry, and pyramidal neuron numbers in female rats. MethodsTwenty-one rats were randomly divided into three groups. The control group received normal nutrition and underwent no procedures. The sham group received intraperitoneal physiological serum, while the experimental group received intraperitoneal 0.8 g/kg fenthion. Rats were sacrificed 24 h after these procedures. The brains were removed and divided in two halves medially, with one side being kept in 10% neutral formalin. After fixation procedures, tissues were embedded in blocks, sliced, and stained. A neuron count was then performed for the hippocampus. The other hippocampus was homogenized and used for biochemical procedures. ResultsHippocampus sections from rats in the experimental group exhibited swelling and loss of shape in pyramidal cells, while no changes were observed in the control or sham groups. The number of neurons in the experimental group was lower than in the control and sham groups. Biochemical analysis revealed higher MDA and GSH values in the experimental group compared to the control and sham groups. ConclusionOur results show increased apoptotic neurodegeneration of cells in the cornu ammonis region of the hippocampus and changes in biochemical values in rats with acute organophosphate exposure.

Association of Organophosphate Pesticide Exposure and a Marker of Asthma Morbidity in an Agricultural Community

ABSTRACTObjectives: We explored the short-term impact of pesticide exposure on asthma exacerbation among children with asthma in an agricultural community.Methods: We obtained repeated urine samples from a subset of 16 school-age children with asthma (n = 139 samples) as part of the Aggravating Factors of Asthma in a Rural Environment (AFARE) study cohort. Biomarkers of organophosphate (OP) pesticide exposure (dialkylphosphates (DAPs)), and asthma exacerbation (leukotriene E4 (uLTE4)) were assessed in urine samples. We used generalized estimating equations to examine the association of summed measures of creatinine-adjusted DAPs (total dimethyl alkylphosphate (EDM), total diethyl alkylphosphate (EDE), and total dialkylphosphate pesticides (EDAP)) and uLTE4 concentration, adjusting for multiple confounders, yielding beta-coefficients with 95% CIs.Results: A total of 139 observations were obtained from the 16 children over the study period, the total number of samples per subject ranged from 1 to 12 (median: 10.5). The geometric mean (GM) of creatinine-adjusted EDE, EDM, and EDAP in this population were 81.0, 71.8 and 168.0 nmol/g, respectively. Increase in uLTE4 levels was consistently associated with increased exposures to DAPs (interquartile range in μg/g): βEDE: 8.7 (95%CI: 2.8, 14.6); βEDM: 1.1 (0.5, 1.7); βEDAP: 4.1 (0.7, 7.5).Conclusion: This study suggests that short-term OP exposure is associated with a higher risk of asthma morbidity, as indicated by increased uLTE4 levels in this cohort of children with asthma in an agricultural community. Additional studies are required to confirm these adverse effects, and explore the mechanisms underlying this relationship.

Antiseizure and neuroprotective effects of delayed treatment with midazolam in a rodent model of organophosphate exposure.

Exposure to organophosphates (OPs) and OP nerve agents (NAs) causes status epilepticus (SE) and irreversible brain damage. Rapid control of seizure activity is important to minimize neuronal injury and the resulting neurological and behavioral disorders; however, early treatment will not be possible after mass release of OPs or NAs. We utilized a delayed-treatment model of OP exposure in adult rats by administration of diisopropyl fluorophosphate (DFP) to study the relationship between the antiseizure and neuroprotective effects of the "standard-of-care" benzodiazepine, midazolam (MDZ), when given at 30, 60, and 120minutes after SE onset. After electroencephalography (EEG) recordings, neural damage in serial brain sections was studied with Fluoro-Jade B staining. MDZ-induced seizure suppression was equivalent in magnitude regardless of treatment delay (ie, seizure duration). When assessed globally (ie, normalized across 10 different brain regions) for each treatment delay, MDZ administration resulted in only nonsignificant reductions in neuronal death. However, when data for MDZ treatment were combined from all three delay times, a small but significant reduction in global neuronal death was detected when compared to vehicle treatment, which indicated that the substantive MDZ-induced seizure suppression led to only a small reduction in neuronal death. In conclusion, MDZ significantly reduced DFP-induced SE intensity when treatment was delayed 30, 60, and even up to 120minutes; however, this reduction in seizure intensity had no detectable effect on neuronal death at each individual delay time. These data show that although MDZ suppressed seizures, additional neuroprotective therapies are needed to mitigate the effects of OP exposure.

Early Synaptic Alterations and Selective Adhesion Signaling in Hippocampal Dendritic Zones Following Organophosphate Exposure

Organophosphates account for many of the world’s deadliest poisons. They inhibit acetylcholinesterase causing cholinergic crises that lead to seizures and death, while survivors commonly experience long-term neurological problems. Here, we treated brain explants with the organophosphate compound paraoxon and uncovered a unique mechanism of neurotoxicity. Paraoxon-exposed hippocampal slice cultures exhibited progressive declines in synaptophysin, synapsin II, and PSD-95, whereas reduction in GluR1 was slower and NeuN and Nissl staining showed no indications of neuronal damage. The distinctive synaptotoxicity was observed in dendritic zones of CA1 and dentate gyrus. Interestingly, declines in synapsin II dendritic labeling correlated with increased staining for β1 integrin, a component of adhesion receptors that regulate synapse maintenance and plasticity. The paraoxon-induced β1 integrin response was targeted to synapses, and the two-fold increase in β1 integrin was selective as other synaptic adhesion molecules were unchanged. Additionally, β1 integrin–cofilin signaling was triggered by the exposure and correlations were found between the extent of synaptic decline and the level of β1 integrin responses. These findings identified organophosphate-mediated early and lasting synaptotoxicity which can explain delayed neurological dysfunction later in life. They also suggest that the interplay between synaptotoxic events and compensatory adhesion responses influences neuronal fate in exposed individuals.

Simultaneous photoreduction and Raman spectroscopy of red blood cells to investigate the effects of organophosphate exposure.

Simultaneous photoreduction and Raman spectroscopy with 532 nm laser has been used to study the effects of organophosphate (chlorpyrifos [CPF]) exposure on human red blood cells (RBCs). Since in RBCs, auto-oxidation causes oxidative stress, which, in turn, is balanced by the cellular detoxicants, any possible negative effect of CPF on this balance should results in an increased level of damaged (permanently oxygenated) hemoglobin. Therefore, when 532 nm laser, at a suitable power, was applied to photoreduce the cells, only common oxygenated form of hemoglobin got photoreduced leaving the permanently oxygenated hemoglobin detectable in the Raman spectra simultaneously excited by the same laser. Using the technique effects of CPF to build up oxidative stress on RBCs could be detected at concentrations as low as 10 ppb from a comparison of relative strengths of different Raman bands. Experiments performed using simultaneously exposing the cells, along with CPF, to H2 O2 (oxidative agent) and/or 3-Aminotriazole (inhibitor of anti-oxidant catalase), suggested role of CPF to suppress the cellular anti-oxidant mechanism. Since the high level of damaged hemoglobin produced by the action of CPF (at concentrations >100 ppm) is expected to cause membrane damage, atomic force microscopy (AFM) was used to identify such damages.Upper panel: Raman spectra of normal, photoreduced CPF exposed and unexposed RBCs. Lower panel: The weak Fe-O2 Raman band for CPF exposed cells shown on the left. The AFM images of unexposed and exposed cells are shown on the right. Scale bar, 2.5 μm.

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer\u2019s disease

Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer’s disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females. The effect on neurodegeneration was more severe in males, and was also associated with accelerated cognitive impairment. Females did not exhibit accelerated cognitive impairment after CPF exposure, and amyloid deposition and tauopathy were unchanged in both males and females. Microglial dysregulation may mediate the increased risk of AD associated with occupational organophosphate exposure, and future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.

Intra-individual variations of organophosphate pesticide metabolite concentrations in repeatedly collected urine samples from pregnant women in Japan

BackgroundLow-dose exposure to organophosphate (OP) insecticides during pregnancy may adversely affect neurodevelopment in children. To evaluate the OP exposure levels, single urine sampling is commonly adopted to measure the levels of dialkylphosphates (DAPs), common OP metabolites. However, the inter-day variations of urinary DAP concentrations within subjects are supposed to be large due to the short biological half-lives of the metabolites, and it is thus considered difficult to accurately assess OP exposure during pregnancy with single sampling. This study aimed to assess intra-individual variations of DAP concentrations and the reproducibility of the exposure dose categorization of OPs according to DAP concentration ranges in pregnant women in Japan.MethodsUrine samples were collected from 62 non-smoking pregnant women (12–22 weeks of gestation) living in Aichi Prefecture, Japan. First morning void (FMV) and spot urine samples taken between lunch and dinner on the same day were collected on five different days during 2 weeks. The concentrations of DAP and creatinine in urine samples were measured using an ultra performance liquid chromatography with tandem mass spectrometry. Creatinine-adjusted and unadjusted concentrations were used for the intraclass correlation coefficient (ICC) calculations and surrogate category analyses.ResultsFor all DAP metabolites, the creatinine-adjusted single ICCs exceeded 0.4, indicating moderate reliability. Overall, ICCs of spot urine samples taken in the afternoon were better than those taken as FMV. Surrogate category analyses showed that participants were categorized accurately into four exposure dose groups according to the quartile points.ConclusionThis study indicated that a single urine sample taken in the afternoon may be useful in assessing OP exposure as long as the exposure is categorized into quartiles when conducting epidemiological studies in early to mid-pregnant women in Japan.

Changes of Thyroid Hormonal Status in Organophosphate Exposure A systematic literature review

Organophosphates (OP) are widely used in both agriculture and household settings as pesticides. Human exposure is mainly due to residues in food or living environment and the main mechanism of OP toxicity are the acetylcholinesterase (AChE) inhibition. Acute poisoning is associated with a high rate of mortality due to parasympathetic overstimulation. In long-term exposure, OP are linked to systemic damage occurrence like nervous, hepatic or renal dysfunction. These compounds are considered as potential endocrine disrupters, causing significant hormonal imbalance targeting the adrenals or thyroid glands. The aim of this article is to review current data in the literature regarding effects of both acute and chronic OP exposure on thyroid hormonal status.