Chronic Organophosphate Exposure Research Articles

Increased Thyroid Hormone Levels in Pesticide Sprayer at Agricultural Area

Pesticides still used massively in the agricultural sector would cause many poisoning and serious health problems. Organophosphate pesticides have been identified as endocrine-disrupting chemicals. This study aimed to analyze the comparison of thyroid hormone levels between the sprayers chronically exposed to pesticides and the control respondents who had never been exposed to pesticides. This study was an analytical observational with a cross-sectional design. The total number of respondents was 150, 50 as sprayers and 100 as control respondents. The venous blood samples were examined using the Enzyme-Linked Immunosorbent Assay (ELISA). The findings significantly showed that the sprayer had a higher level of thyroid-stimulating hormone (TSH) (4.776 ± 1.1166), lower triiodothyronine (T3) (108.822 ± 18.810), and lower thyroxine (T4) (7.808 ± 1.067). Determinant factors among sprayers that significantly correlated to TSH levels was (age = 0.006; work duration = 0.000; PPE = 0.045; body position = 0.014; type of pesticides = 0.004), correlated with T3 levels was (age = 0.037; body position = 0.045), correlated with T4 levels was (age = 0.000; PPE = 0.045). It could be concluded that chronic organophosphate exposure would increase TSH and decrease T3 and T4.

Towards epigenomic and metabolomic profiles of chronic organophosphate exposure in residents of California’ Central Valley

BACKGROUND AND AIM: Organophosphates (OP) are widely used in the agricultural Central Valley region of California. This study aimed to elucidate metabolomic and epigenetic changes induced by chronic ambient OP exposure, as well as possible interactions between different molecular layers. METHODS: We conducted high-resolution metabolomic profiling (liquid chromatography with high-resolution mass spectrometry) and genome-wide DNA methylation profiling (Illumina 450 k) of blood samples from 176 older adults living in the California Central Valley. Cumulative OP exposure from ambient sources at homes and workplaces over a ten-year period was estimated using a geographic information system (GIS)-based model. Biweighted midcorrelation (bicor) and partial least squares regression were used to identify metabolomic features and CpGs associated with OPs. Potential confounders, including age, sex, race/ethnicity, education, and cell compositions, were adjusted a prior. Functional annotation and pathway enrichment analyses were conducted for biological interpretation. We also integrated the methylome and metabolome by investigating the correlation structures existing between OP-related CpGs and metabolites and all other features via bicor. RESULTS:The single-omic analyses showed both epigenomic and metabolomic signatures of OP as being enriched in the glycosphingolipid (GSL) biosynthesis pathway. Besides this common pathway, the metabolome and epigenome also exhibited distinct responses to OPs, with differently methylated CpGs being involved in intracellular membrane transport, cell adhesion, and carcinogenesis; and OP-related metabolites being involved in aromatic amino acids metabolism, neurotransmitter precursors, oxidative stress, and mitochondria function. Moreover, we illustrate possible interactions between these two molecular layers through metabolic processes and nutrient-sensing pathways when integrating the epigenomic and metabolomic signals. CONCLUSIONS:In summary, we linked GIS-modeled chronic low-level OP pesticide data with blood metabolomic and epigenomic data in an older adult population. Our findings suggest that it seems feasible to use multi-omics integration in studies of chronic environmental exposures in humans to better understand the pathophysiology involved in pesticide-related chronic health outcomes. KEYWORDS: Organophosphates, multi-omics, metabolomics, epigenomics, glycosphingolipid

Association between Organophosphate Pesticide Exposure and Insulin Resistance in Pesticide Sprayers and Nonfarmworkers.

Insulin resistance is a risk factor for various diseases. Chronic organophosphate exposure has been reported to be a cause of insulin resistance in animal models. This cross-sectional study aimed to evaluate the association between organophosphate exposure and insulin resistance in pesticide sprayers and nonfarmworkers. Participants aged 40–60 years, consisting of 150 pesticide sprayers and 150 nonfarmworkers, were interviewed and assessed for their homeostatic model assessment of insulin resistance (HOMA-IR) level. Organophosphate (OP) exposure was measured in 37 sprayers and 46 nonfarmworkers by first morning urinary dialkyl phosphate (DAP) metabolites. The DAP metabolite levels were not different in either group except for diethylthiophosphate (DETP; p = 0.03), which was higher in sprayers. No significant association was observed between DAP metabolite levels and HOMA-IR. Wearing a mask while handling pesticides was associated with lower dimethyl metabolites (95% CI = −11.10, −0.17). Work practices of reading pesticide labels (95% CI = −81.47, −14.99) and washing hands after mixing pesticide (95% CI = −39.97, −3.35) correlated with lower diethyl alkylphosphate level. Overall, we did not observe any association between OP exposure and insulin resistance in pesticide sprayers and the general population. However, personal protective equipment (PPE) utilization and work practice were associated with OP exposure level in sprayers.

Metabolome-wide association study of organophosphate pesticide exposure

Background: Organophosphates (OP) are widely used insecticides that acutely inhibit acetylcholinesterase enzyme activity. There is great interest in improving the understanding of molecular mechanisms related to chronic OP exposure induced toxicity. We aim to elucidate metabolomic changes associated with OP exposure using high-resolution metabolomics (HRM).Methods: In a population-based case control study of Parkinson's disease (PD), we retrieved serum samples of 178 controls and assessed ambient OP exposure via residential and workplace proximity to commercial applications for each subject. We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares regression to select metabolic features associated with OP exposure. Pathway analyses were employed to identify biologic pathways related to OP exposure. Confounders including age, race/ethnicity, sex were controlled a prior.Results: In total we extracted 8,615 and 4,124 metabolic features from serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. Controlling for confounding factors, 151 and 50 discriminatory metabolic features (HILIC and C18, respectively) were selected (Variable Importance in Projection (VIP) >= 2). Pathway enrichment analysis for discriminatory features associated with OP indicated that in serum fatty acid oxidation and inflammation related pathways were altered, including arachidonic acid, leukotriene, and prostaglandin pathways.Conclusion: This study finds chronic low-level OP exposure is associated with differential metabolomic profiles in serum. Our study results suggest that long-term sub-acute OP exposure influences metabolites enriched for oxidative stress and inflammation pathways.

Oxidative Stress and Analysis of Selected SNPs of ACHE (rs 2571598), BCHE (rs 3495), CAT (rs 7943316), SIRT1 (rs 10823108), GSTP1 (rs 1695), and Gene GSTM1, GSTT1 in Chronic Organophosphates Exposed Groups from Cameroon and Pakistan.

The detrimental effects of organophosphates (OPs) on human health are thought to be of systemic, i.e., irreversible inhibition of acetylcholinesterase (AChE) at nerve synapses. However, several studies have shown that AChE inhibition alone cannot explain all the toxicological manifestations in prolonged exposure to OPs. The present study aimed to assess the status of antioxidants malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) (reduced), catalase, and ferric reducing antioxidant power (FRAP) in chronic OP-exposed groups from Cameroon and Pakistan. Molecular analysis of genetic polymorphisms (SNPs) of glutathione transferases (GSTM1, GSTP1, GSTT1), catalase gene (CAT, rs7943316), sirtuin 1 gene (SIRT1, rs10823108), acetylcholinesterase gene (ACHE, rs2571598), and butyrylcholinesterase gene (BCHE, rs3495) were screened in the OP-exposed individuals to find the possible causative association with oxidative stress and toxicity. Cholinesterase and antioxidant activities were measured by colorimetric methods using a spectrophotometer. Salting-out method was employed for DNA extraction from blood followed by restriction fragment length polymorphism (RFLP) for molecular analysis. Cholinergic enzymes were significantly decreased in OP-exposed groups. Catalase and SOD were decreased and MDA and FRAP were increased in OP-exposed groups compared to unexposed groups in both groups. GSH was decreased only in Pakistani OPs-exposed group. Molecular analysis of ACHE, BCHE, Catalase, GSTP1, and GSTM1 SNPs revealed a tentative association with their phenotypic expression that is level of antioxidant and cholinergic enzymes. The study concludes that chronic OPs exposure induces oxidative stress which is associated with the related SNP polymorphism. The toxicogenetics of understudied SNPs were examined for the first time to our understanding. The findings may lead to a newer area of investigation on OPs induced health issues and toxicogenetics.

Organophosphate exposure and the chronic effects on farmers: a narrative review.

Organophosphates are a class of insecticides used globally by the agricultural industry for insect control. Acute consequences of organophosphate exposures are well known, while there has been limited research on their long-term effects. The objective of this review was to discuss the health effects of chronic organophosphate exposure in farmers. Medline, Scopus and Web of Science were searched to find the relevant articles. Articles published only in English and until December 2018 were reviewed. The selected articles were then categorised as neurological (neurobehaviour, neurodevelopmental, neurological signs and symptoms) or non-neurological subheadings. A total of 53 articles for neurological effects and 17 articles for non-neurological effects were identified. Chronic organophosphates exposure was associated with deficits in the neurobehaviour subsets of attention and short-term memory, increased incidence of neurodegenerative diseases and effects on peripheral nerves and neurodevelopment. However, research to support non-neurological effects such as respiratory symptoms, increased cancer risk, endocrine disruption, cardiac issues, chronic fatigue and infertility was limited. Chronic organophosphate exposure was found to affect four of the five areas of described neurological effects in the literature. A large proportion of the research in this area was not methodologically strong, therefore few recommendations can be conclusively made. Future research is warranted to investigate the non-neurological effects of chronic exposure to ensure the occupational risks of low-level chronic exposure are clearly communicated to farmers and farm workers.

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.

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.

Chronic organophosphate exposure triggers ROS-mediated injuries at organismal and sub-organismal levels of non-target Drosophila melanogaster

Chronic organophosphate exposure triggers ROS-mediated injuries at organismal and sub-organismal levels of non-target Drosophila melanogaster

Aortic Elasticity Profile of Children Living in Area of Chronic Organophosphate Exposure: A Preliminary Study

Brebes is an agricultural village in north coastal area of Central Java that is exposed to organophosphate pesticides. Organophosphate could cause mechanical damage of artery such as increasing the stiffness and leading to arteriosclerosis in early life. Aortic (Ao) elasticity profiles of children who are living in those polluted area have never been studied. The aim of study was to determine Ao wall stiffness and distensibility in children living in Brebes. A cross sectional study was conducted in fifty students aged 9-12 years (mean 9.24 SD 0.69), male 30 and 20 female, who were living in Brebes. Ascending Ao distensibillity and stiffness were obtained on M-mode using Logic E echocardiography. Mean value of three times measurement was presented and compared with standard for healthy children according to the age. Mean and median of Ao-distensibility were 98.7 (SD 55.08) and 90.8 (13.98-224.55) [normal 97.1 (SD 47.6); 85.7 (22.6-368.5)]; Ao-stiffness index were 2.2 (SD 0.55) and 2.1 (1.28-4.06) [1.18 (SD 0.57); 1.05 (0.24-3.69)] respectively. Ao distensibility of subjects showed 16% lower, 62% normal and 20% higher than the mean of standard value. Ao stiffness index of subjects was 16% normal and 84% higher than standard. After adjusted with BSA, 78% of subject's Ao distensibility/BSA was normal, 96% has higher Ao stiffness index/BSA than mean standard value. This study found higher Ao-stiffness index among children living in organophosphate exposure area, despite of normal Ao distensibility.

Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity

Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.

Organophosphate intermediate syndrome with neurological complications of extrapyramidal symptoms in clinical practice.

Organophosphates (OPs) are ubiquitous in the world as domestic and industrial agricultural insecticides. Intentional poisoning as suicides attempts are clinical phenomena seen in emergency departments and clinics in agricultural areas. Intermediate syndrome with the neurological complication of extra pyramidal symptoms following acute OP ingestion may occur in pediatric and adult cases. While death is the most serious consequence of toxic OP doses, low levels of exposure and nonfatal doses may disrupt the neurobehavioral development of fetuses and children in addition to bring linked to testicular cancer and male and female infertility. These are disturbing. Chronic and acute toxicity from OPs are barriers to the health of our present and future generations. Symptoms and treatment of acute and chronic OP exposure are briefly referenced with inclusion of the intermediate syndrome. Suggestions for local and systemic reduction of the acute and long term consequences of OP ingestion are opined.

1H Nuclear Magnetic Resonance (NMR) Metabolomic Study of Chronic Organophosphate Exposure in Rats.

1H NMR spectroscopy and chemometric analysis were used to characterize rat urine obtained after chronic exposure to either tributyl phosphate (TBP) or triphenyl phosphate (TPP). In this study, the daily dose exposure was 1.5 mg/kg body weight for TBP, or 2.0 mg/kg body weight for TPP, administered over a 15-week period. Orthogonal signal correction (OSC) -filtered partial least square discriminant analysis (OSC-PLSDA) was used to predict and classify exposure to these organophosphates. During the development of the model, the classification error was evaluated as a function of the number of latent variables. NMR spectral regions and corresponding metabolites important for determination of exposure type were identified using variable importance in projection (VIP) coefficients obtained from the OSC-PLSDA analysis. As expected, the model for classification of chronic (1.5–2.0 mg/kg body weight daily) TBP or TPP exposure was not as strong as the previously reported model developed for identifying acute (15–20 mg/kg body weight) exposure. The set of majorly impacted metabolites identified for chronic TBP or TPP exposure was slightly different than those metabolites previously identified for acute exposure. These metabolites were then mapped to different metabolite pathways and ranked, allowing the metabolic response to chronic organophosphate exposure to be addressed.

Mitochondrial energy metabolism impairment and liver dysfunction following chronic exposure to dichlorvos

Although the effects of acute pesticide poisoning are well known but, hardly any data exists regarding the health effects after long-term low-level exposure. Major unresolved issues include the effect of moderate exposure in the absence of poisoning. The present study elucidates a possible mechanism by which chronic organophosphate exposure (dichlorvos 6 mg/kg b.wt., s.c. for 12 weeks) causes liver dysfunction. Mitochondria, a primary site of cellular energy generation and oxygen consumption represent a likely target for organophosphate poisoning. Therefore, the objective of the current study was planned with an aim to investigate the effect of chronic dichlorvos exposure on liver mitochondrial electron transport chain (ETC), mitochondrial calcium uptake and its implications on the induction of liver enzymes and liver dysfunction in rodent model. Our results indicated decreased mitochondrial electron transfer activities of cytochrome oxidase along with altered mitochondrial complexes I and II activity. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria isolated from dichlorvos (DDVP) treated rat liver. Mitochondrial preparation from DDVP treated rat liver demonstrated significant increase in mitochondrial Ca 2+ uptake and increase ROS levels. The alterations in the mitochondrial calcium uptake, mitochondrial electron transfer enzyme activities and increase ROS levels in turn might have caused an increase in liver enzymes (ALT, AST and ALP). The electron micrographs of liver cells depicted morphological changes in mitochondria as well as nucleus following 12 weeks of exposure to DDVP. These studies provide an evidence of impaired mitochondrial bioenergetics which may lead to liver dysfunction after chronic exposure to dichlorvos.

Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain

The present study elucidates a possible mechanism by which chronic organophosphate exposure (dichlorvos 6 mg/kg bw, s.c. for 12 weeks) causes neuronal degeneration. Mitochondria, as a primary site of cellular energy generation and oxygen consumption represent itself a likely target for organophosphate poisoning. Therefore, the objective of the current study was planned with an aim to investigate the effect of chronic dichlorvos exposure on mitochondrial calcium uptake, oxidative stress generation and its implication in the induction of neuronal apoptosis in rodent model. Mitochondrial preparation from dichlorvos (DDVP) treated rat brain demonstrated significant increase in mitochondrial Ca 2+ uptake (644.2 nmol/mg protein). Our results indicated decreased mitochondrial electron transfer activities of cytochrome oxidase (complex IV) along with altered mitochondrial complex I, and complex II activity, which might have resulted from elevated mitochondrial calcium uptake. The alterations in the mitochondrial calcium uptake and mitochondrial electron transfer enzyme activities in turn might have caused an increase in malondialdehyde, protein carbonyl and 8-hydoxydeoxyguanosine formation as a result of enhanced lipid peroxidation, and as well as protein and mtDNA oxidation. All this could have been because of enhanced oxidative stress, decreased GSH levels and also decreased Mn-SOD activity in the mitochondria isolated from dichlorvos treated rat brain. Thus, chronic organophosphate exposure has the potential to disrupt cellular antioxidant defense system which in turn triggers the release of cytochrome c from mitochondria to cytosol as well as caspase-3 activation in dichlorvos treated rat brain as revealed by immunoblotting experiments. Low-level long-term organophosphate exposure finally resulted in oligonucleosomal DNA fragmentation, a hallmark of apoptosis. These studies provide an evidence of impaired mitochondrial bioenergetics and apoptotic neuronal degeneration after chronic low-level exposure to dichlorvos.

Suicide and exposure to organophosphate insecticides: Cause or effect?

Suicide using pesticides as agent is recognized as a major cause of pesticide poisoning. A literature review of mortality and morbidity studies related to suicide among pesticide-exposed populations, and of human and animal studies of central nervous system toxicity related to organophosphate (OP) pesticides was performed. Suicide rates are high in farming populations. Animal studies link OP exposure to serotonin disturbances in the central nervous system, which are implicated in depression and suicide in humans. Epidemiological studies conclude that acute and chronic OP exposure is associated with affective disorders. Case series and ecological studies also support a causal association between OP use and suicide. OPs are not only agents for suicide. They may be part of the causal pathway. Emphasizing OPs solely as agents for suicide shifts responsibility for prevention to the individual, reducing corporate responsibility and limiting policy options available for control.

The effects of acute pesticide exposure on neuroblastoma cells chronically exposed to diazinon

Speculation about potential neurotoxicity due to chronic exposure to low doses of organophosphate (OP) pesticides is not yet supported by experimental evidence. The objective of this work was to use a cell culture model of chronic OP exposure to determine if such exposure can alter the sensitivity of nerve cells to subsequent acute exposure to OPs or other compounds. NB2a neuroblastoma cells were grown in the presence of 25 μM diazinon for 8 weeks. The OP was then withdrawn and the cells were induced to differentiate in the presence of various other pesticides or herbicides, including OPs and OP-containing formulations. The resulting outgrowth of neurite-like structures was measured by light microscopy and quantitative image analysis and the IC 50 for each OP or formulation was calculated. The IC 50 values in diazinon-pre-exposed cells were compared with the equivalent values in cells not pre-exposed to diazinon. The IC 50 for inhibition of neurite outgrowth by acute application of diazinon, pyrethrum, glyphosate or a commercial formulation of glyphosate was decreased by between 20 and 90% after pre-treatment with diazinon. In contrast, the IC 50 for pirimiphos methyl was unaffected and those for phosmet or chlorpyrifos were increased by between 1.5- and 3-fold. Treatment of cells with chlorpyrifos or with a second glyphosate-containing formulation led to the formation of abnormal neurite-like structures in diazinon-pre-exposed cells. The data support the view that chronic exposure to an OP may reduce the threshold for toxicity of some, but by no means all, environmental agents.

Reduced bone formation after exposure to organophosphates

Bone histomorphometric analysis in 24 agricultural workers with chronic organophosphate exposure showed significantly lower bone formation at tissue and cellular level than in healthy controls.

Chronic Organophosphate Exposure: Towards the Definition of a Neuropsychiatric Syndrome

The clinical features of 33 patients with significant histories of chronic exposure to organophosphate pesticides (OPs) are reported. Disorders of mood, cognition, perception and motor performance are consistently linked to the point that it is suggested that a distinct and specific syndrome of neuropsychiatric disorder resulting from chronic OP exposure exists and tentative operational criteria for its diagnosis are proposed. Attention is drawn to the fact that this syndrome differs significantly from chronic fatigue syndrome (myalgic encephalitis) both in terms of the nature of symptoms reported and in particular the difference in consistency of reporting.

Occupational Exposure to Organophosphate Pesticides

Acute organophosphate intoxication in man is well known to result in substantial central nervous system dysfunction. To test the hypothesis that similar neurobehavioral abnormalities might be present in mild degree in workers chronically exposed to organophosphate pesticides, 23 such subjects were tested for abnormalities in memory, signal processing, vigilance, language, and proprioceptive feedback performance. The performance of the exposed workers was not deficient in any of the five measures assessed when compared with the performance of a control group matched for age and educational background. Plasma and red blood cell cholinesterase levels were found to be in the normal range in both exposed and control groups, although plasma levels of exposed subjects were depressed somewhat below control values. Relative resistance of higher nervous system functions to mild chronic organophosphate exposure is suggested by these results.