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Neurochemical Research Jan 2021Organophosphate (OP) compounds are widely used as pesticides and herbicides and exposure to these compounds has been associated with both chronic and acute forms of...
Organophosphate (OP) compounds are widely used as pesticides and herbicides and exposure to these compounds has been associated with both chronic and acute forms of neurological dysfunction including cognitive impairment, neurophysiological problems and cerebral ataxia with evidence of mitochondrial impairment being associated with this toxicity. In view of the potential mitochondrial impairment, the present study aimed to investigate the effect of exposure to commonly used OPs, dichlorvos, methyl-parathion (parathion) and chloropyrifos (CPF) on the cellular level of the mitochondrial electron transport chain (ETC) electron carrier, coenzyme Q (CoQ) in human neuroblastoma SH-SY5Y cells. The effect of a perturbation in CoQ status was also evaluated on mitochondrial function and cell viability. A significant decreased (P < 0.0001) in neuronal cell viability was observed following treatment with all three OPs (100 µM), with dichlorvos appearing to be the most toxic to cells and causing an 80% loss of viability. OP treatment also resulted in a significant diminution in cellular CoQ status, with levels of this isoprenoid being decreased by 72% (P < 0.0001), 62% (P < 0.0005) and 43% (P < 0.005) of control levels following treatment with dichlorvos, parathion and CPF (50 µM), respectively. OP exposure was also found to affect the activities of the mitochondrial enzymes, citrate synthase (CS) and mitochondrial electron transport chain (ETC) complex II+III. Dichlorvos and CPF (50 µM) treatment significantly decreased CS activity by 38% (P < 0.0001) and 35% (P < 0.0005), respectively compared to control levels in addition to causing a 54% and 57% (P < 0.0001) reduction in complex II+III activity, respectively. Interestingly, although CoQ supplementation (5 μM) was able to restore cellular CoQ status and CS activity to control levels following OP treatment, complex II+III activity was only restored to control levels in neuronal cells exposed to dichlorvos (50 µM). However, post supplementation with CoQ, complex II+III activity significantly increased by 33% (P < 0.0005), 25% (P < 0.005) and 35% (P < 0.0001) in dichlorvos, parathion and CPF (100 µM) treated cells respectively compared to non-CoQ supplemented cells. In conclusion, the results of this study have indicated evidence of neuronal cell CoQ deficiency with associated mitochondrial dysfunction following OP exposure. Although CoQ supplementation was able to ameliorate OP induced deficiencies in CS activity, ETC complex II+III activity appeared partially refractory to this treatment. Accordingly, these results indicate the therapeutic potential of CoQ supplementation in the treatment of OP poisoning. However, higher doses may be required to engender therapeutic efficacy.
Topics: Cell Line, Tumor; Cell Survival; Chlorpyrifos; Dichlorvos; Electron Transport Complex II; Electron Transport Complex III; Humans; Insecticides; Methyl Parathion; Mitochondria; Neurons; Ubiquinone
PubMed: 32306167
DOI: 10.1007/s11064-020-03033-y -
Journal of Medical Toxicology :... Dec 2018The gap between the number of patients on transplant waiting lists and patients receiving transplants is growing. Use of organs from donors who have died following... (Review)
Review
INTRODUCTION
The gap between the number of patients on transplant waiting lists and patients receiving transplants is growing. Use of organs from donors who have died following pesticide exposure remains controversial. This study reviews the literature related to transplantation from this group.
METHODS
A literature search was undertaken on PubMed using the following keywords: 'insecticide', 'pesticide', 'rodenticide', 'organophosphate', 'carbamate', 'paraquat', 'poisoning', 'toxicity', 'overdose', 'intoxication', 'ingestion', 'organ donation or procurement', 'transplant', 'allograft transplant', and 'expanded criteria organ donation'; 21 specific pesticides/insecticides were also added to the search; the indexes for EAPCCT/NACCT meeting abstracts 2008-2017 were also searched. Identified publications were reviewed and if described human donation/transplantation of ≥ 1 solid organ(s), the following was extracted: (i) compound(s) ingested; (ii) donor demographics; (iii) organ(s) transplanted; and (iv) graft function at follow-up.
RESULTS
Ten papers were identified describing 20 fatalities (1999-2017) related to the following pesticide exposures: organophosphate, 8 cases; aldicarb, 4; paraquat, 3; parathion, 1; malathion, 1; carbofuran/carbamate, 1; carbamate, 1; and brodifacoum, 1 and no further cases were identified from EAPCCT/NACCT abstracts. Donors were aged 12-50 (25.9 ± 11.9) years. Forty-four organs were transplanted: 28 kidneys, 7 livers, 6 corneas, and 3 hearts. Forty recipients had outcome reported: 3 (7.5%) patients died, 3 (7.5%) had graft failure/dysfunction and 34 (85.0%) had good graft function. Overall survival with good function was 96%, 71%, 83%, and 67% for kidneys, livers, corneas and hearts respectively.
CONCLUSION
Review of the published literature suggests that solid organ donation following exposure to a pesticide is associated with good short-to-medium-term graft organ function following transplantation, particularly for transplanted kidneys and corneas.
Topics: Humans; Organ Transplantation; Pesticides; Tissue Donors; Treatment Outcome
PubMed: 29987646
DOI: 10.1007/s13181-018-0673-5 -
Environmental Research Nov 2022Organophosphate (OP) and pyrethroid pesticides (PYR) are extensively used in agriculture, resulting in higher exposures among farmworkers. The present study reports the...
Organophosphate (OP) and pyrethroid pesticides (PYR) are extensively used in agriculture, resulting in higher exposures among farmworkers. The present study reports the occurrence of 8 urinary OP and PYR metabolites in a sample of farmworkers and residents from Sucs (n = 87), a rural township in North West Catalonia (Spain). The aim of the present study was to examine differences in urinary pesticide metabolite concentrations between occupationally-exposed (farmworkers; n = 45) and environmentally-exposed subjects (n = 42) and to assess the relationship between pesticide's exposures and occupational activities in a real-case scenario. Six OP and two PYR metabolites have been investigated, urine samples were extracted using SPE extraction and analyzed by UPLC-MS/MS. Three OP metabolites were commonly detectable in urine, namely TCPY (metabolite of chlorpyrifos), PNP (parathion) and DEAMPY (pirimiphos). Regarding pyrethroids, the two analyzed metabolites, 3-PBA and 4F-3-PBA, were detected in a high proportion of urine samples. Differences in concentrations between both groups were statistically significant for TCPY and 4F-3-PBA (Mann-Whitney U Test for independent groups, p < 0.05). In the case of TCPY, the concentrations were higher among the farmworkers, which is consistent with their occupational activity. The small differences found in DEAMPY, PNP, 3-PBA or even the significant higher concentrations of 4F-3-PBA among rural population suggest a general exposure to these compounds, even in those who do not carry an occupational activity. Specific personal protective equipment (PPE) among farmworkers, such as the use of gloves and mask during mixing, showed a decrease in the exposure levels, although the differences were not statistically significant. However, a positive association was found between the use of a cap during mixing (for PNP and 3-PBA) and during application (only for 3-PBA). However, this piece of cloth is mainly used for sun protection, and when not cleaned after the handling of pesticides, it might represent a continuous source of exposure through dermal contact. Farmworkers using tractors with cabin had statistically significant lower concentrations of DEAMPY than those using a tractor without cabin. The previous results suggest that occupational protections should be encouraged among farmworkers and other potential workers handling with pesticides.
Topics: Agriculture; Chlorpyrifos; Chromatography, Liquid; Humans; Occupational Exposure; Pesticides; Pyrethrins; Rural Population; Tandem Mass Spectrometry
PubMed: 36030920
DOI: 10.1016/j.envres.2022.114186 -
Bulletin of the World Health... 1971This paper reviews the distribution of cholinesterases in the central nervous system, the ganglia, the striated muscle, and the blood of mammals, and discusses the... (Review)
Review
This paper reviews the distribution of cholinesterases in the central nervous system, the ganglia, the striated muscle, and the blood of mammals, and discusses the correlation between the histochemical localization and the function of neuronal cholinesterase.Different methods for the determination of cholinesterase levels are reviewed, with particular reference to their practical value for field work. The Warburg method and the Tintometer and Acholest colorimetric methods are compared on the basis of cholinesterase levels determined in normal persons and in those suffering from parathion intoxication.
Topics: Acetylcholinesterase; Animals; Carbon Isotopes; Cats; Central Nervous System; Chemical Phenomena; Chemistry; Choline; Cholinesterases; Colorimetry; Ganglia; Haplorhini; Histocytochemistry; Humans; Hydrogen-Ion Concentration; Manometry; Methods; Muscle, Smooth; Muscles; Parathion; Rabbits; Rats; Species Specificity; Spectrophotometry; Sulfhydryl Compounds
PubMed: 4999484
DOI: No ID Found -
Neurobiology of Disease Jan 2020Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP... (Review)
Review
Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP exposure is associated with a cholinergic crisis and status epilepticus (SE). It is also known that the survivors of OP toxicity exhibit neurobehavioral deficits such as mood changes, depression, and memory impairment, and acquired epilepsy. Our research has focused on addressing the need to develop effective therapeutic agents that could be administered even after prolonged seizures and would prevent or lessen the chronic morbidity associated with OP-SE survival. We have developed rat survival models of OP pesticide metabolite paraoxon (POX) and nerve agent sarin surrogate diisopropyl fluorophosphate (DFP) induced SE that are being used to screen for medical countermeasures against an OP attack. Our research has focused on studying neuronal calcium (Ca) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a "Ca plateau" characterized by sustained elevations in neuronal Ca levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca elevations had their origin in Ca release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca plateau and afforded significant neuroprotection. Since the Ca plateau lasts for a prolonged period, our studies suggest that blocking it after the control of SE may represent a unique target for development of novel countermeasures to prevent long term Ca mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).
Topics: Animals; Brain; Calcium; Depression; Epilepsy; Homeostasis; Memory Disorders; Neurons; Organophosphate Poisoning; Rats; Status Epilepticus
PubMed: 30872159
DOI: 10.1016/j.nbd.2019.03.006 -
Toxicology May 2013Paraoxonase (PON1) is an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon... (Review)
Review
Paraoxonase (PON1) is an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon and chlorpyrifos. PON1 activity is highest in liver and in plasma. Human PON1 displays two polymorphisms in the coding region (Q192R and L55M) and several polymorphisms in the promoter and the 3'-UTR regions. The Q192R polymorphism imparts differential catalytic activity toward some OP substrates, while the polymorphism at position -108 (C/T) is the major contributor of differences in the levels of PON1 expression. Both contribute to determining an individual's PON1 "status". Animal studies have shown that PON1 is an important determinant of OP toxicity. Administration of exogenous PON1 to rats or mice protects them from the toxicity of specific OPs. PON1 knockout mice display a high sensitivity to the toxicity of diazoxon and chlorpyrifos oxon, but not of paraoxon. In vitro catalytic efficiencies of purified PON192 alloforms for hydrolysis of specific oxon substrates accurately predict the degree of in vivo protection afforded by each isoform. Evidence is slowly emerging that a low PON1 status may increase susceptibility to OP toxicity in humans. Low PON1 activity may also contribute to the developmental toxicity and neurotoxicity of OPs, as shown by animal and human studies.
Topics: Animals; Aryldialkylphosphatase; Genetic Predisposition to Disease; Humans; Mice; Organophosphate Poisoning; Polymorphism, Single Nucleotide; Rats
PubMed: 22884923
DOI: 10.1016/j.tox.2012.07.011 -
Environmental Toxicology Jun 2013Methyl parathion (C₈H₁₀NO₅PS) and parathion (C₁₀H14 NO₅PS) are both organophosphate insecticides (OPI) widely used for household and agricultural...
Methyl parathion (C₈H₁₀NO₅PS) and parathion (C₁₀H14 NO₅PS) are both organophosphate insecticides (OPI) widely used for household and agricultural applications. They are known for their ability to irreversibly inhibit acetylcholinesterase which often leads to a profound effect on the nervous system of exposed organisms. Many recently published studies have indicated that human exposure to OPI may be associated with neurologic, hematopoietic, cardiovascular, and reproductive adverse effects. Studies have also linked OPI exposure to a number of degenerative diseases including Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. Also, oxidative stress (OS) has been reported as a possible mechanism of OPI toxicity in humans. Hence, the aim of the present investigation was to use human liver carcinoma (HepG₂) cells as a test model to evaluate the role of OS in methyl parathion- and parathion-induced toxicity. To achieve this goal, we performed the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay for cell viability, lipid peroxidation assay for malondialdehyde (MDA) production, and Comet assay for DNA damage, respectively. Results from MTT assay indicated that methyl parathion and parathion gradually reduce the viability of HepG₂ cells in a dose-dependent manner, showing 48 h-LD₅₀ values of 26.20 mM and 23.58 mM, respectively. Lipid peroxidation assay resulted in a significant increase (P < 0.05) of MDA level in methyl parathion- and parathion-treated HepG₂ cells compared with controls, suggesting that OS plays a key role in OPI-induced toxicity. Comet assay indicated a significant increase in genotoxicity at higher concentrations of OPI exposure. Overall, we found that methyl-parathion is slightly less toxic than parathion to HepG₂ cells. The cytotoxic effect of these OPI was found to be associated, at least in part, with oxidative cell/tissue damage.
Topics: Cell Survival; Comet Assay; DNA Damage; Hep G2 Cells; Humans; Insecticides; Lethal Dose 50; Lipid Peroxidation; Malondialdehyde; Methyl Parathion; Oxidative Stress; Parathion
PubMed: 21544925
DOI: 10.1002/tox.20725 -
Toxicological Sciences : An Official... Feb 2023High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the...
High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the efficacy of human neuroblastoma cell line (SH-SY5Y) to provide molecular and cellular responses characteristic of the OP neurotoxicity pathway was investigated in response to the OP-model compound, ethyl-parathion. Undifferentiated SH-SY5Y cells were exposed to ethyl-parathion for 30 min at 0 (control), 0.5, 2.5, 5, 10, and 25 µg/ml. Dose-responsive reductions in cell viability were observed with significant reductions at ≥10 µg/ml. From these results, ethyl-parathion exposures of 0 (control), 5, and 10 µg/ml were selected to examine bioindicators underlying the OP neurotoxicity pathway including: reactive oxygen species (ROS), cell membrane peroxidation, mitochondrial membrane potential (MMP), and apoptosis. Ethyl-parathion elicited highly significant increases in ROS relative to controls (p < .01) at both exposure concentrations, confirmed using N-acetyl cysteine (NAC) as a ROS quencher which alleviated ROS increases. A response characteristic of increased ROS exposure, cell membrane-lipid peroxidation, significantly increased (p < .05) at the highest ethyl-parathion exposure (10 µg/ml). As a likely consequence of membrane-lipid peroxidation, ethyl-parathion-induced reductions in MMP were observed with significant effects at 10 µg/ml, reducing MMP by 58.2%. As a culmination of these cellular-damage indicators, apoptosis progression was investigated by phosphatidylserine translocation where ethyl-parathion-induced dose-responsive, highly significant (p < .01) increases at both 5 and 10 µg/ml. Overall, the mechanistic responses observed in undifferentiated SH-SY5Y cells corresponded with in vivo mammalian results demonstrating potential for this nonanimal model to provide accurate OP neurotoxicology screening.
Topics: Humans; Reactive Oxygen Species; Parathion; Cell Line, Tumor; Neuroblastoma; Apoptosis; Neurotoxicity Syndromes; Cell Survival
PubMed: 36458919
DOI: 10.1093/toxsci/kfac125 -
Environmental Health : a Global Access... Aug 2022Organophosphate (OP) insecticides represent one of the largest classes of sprayed insecticides in the U.S., and their use has been associated with various adverse health...
BACKGROUND
Organophosphate (OP) insecticides represent one of the largest classes of sprayed insecticides in the U.S., and their use has been associated with various adverse health outcomes, including disorders of blood pressure regulation such as hypertension (HTN).
METHODS
In a study of 935 adults from the NHANES 2013-2014 cycle, we examined the relationship between systolic and diastolic blood pressure changes and urinary concentrations of three OP insecticides metabolites, including 3,5,6-trichloro-2-pyridinol (TCPy), oxypyrimidine, and para-nitrophenol. These metabolites correspond to the parent compounds chlorpyrifos, diazinon, and methyl parathion, respectively. Weighted, multivariable linear regression analysis while adjusting for potential confounders were used to model the relationship between OP metabolites and blood pressure. Weighted, multivariable logistic regression analysis was used to model the odds of HTN for quartile of metabolites.
RESULTS
We observed significant, inverse association between TCPy on systolic blood pressure (β-estimate = -0.16, p < 0.001) and diastolic blood pressure (β-estimate = -0.15, p < 0.001). Analysis with para-nitrophenol revealed a significant, positive association with systolic blood pressure (β-estimate = 0.03, p = 0.02), and an inverse association with diastolic blood pressure (β-estimate = -0.09, p < 0.001). For oxypyrimidine, we observed significant, positive associations between systolic blood pressure (β-estimate = 0.58, p = 0.03) and diastolic blood pressure (β-estimate = 0.31, p < 0.001). Furthermore, we observed significant interactions between TCPy and ethnicity on systolic blood pressure (β-estimate = 1.46, p = 0.0036). Significant interaction terms were observed between oxypyrimidine and ethnicity (β-estimate = -1.73, p < 0.001), as well as oxypyrimidine and BMI (β-estimate = 1.51 p < 0.001) on systolic blood pressure, and between oxypyrimidine and age (β-estimate = 1.96, p = 0.02), race (β-estimate = -3.81 p = 0.004), and BMI on diastolic blood pressure (β-estimate = 0.72, p = 0.02). A significant interaction was observed between para-nitrophenol and BMI for systolic blood pressure (β-estimate = 0.43, p = 0.01), and between para-nitrophenol and ethnicity on diastolic blood pressure (β-estimate = 2.19, p = 0.006). Lastly, we observed a significant association between the odds of HTN and TCPy quartiles (OR = 0.65, 95% CI [0.43,0.99]).
CONCLUSION
Our findings support previous studies suggesting a role for organophosphate insecticides in the etiology of blood pressure dysregulation and HTN. Future studies are warranted to corroborate these findings, evaluate dose-response relationships between organophosphate insecticides and blood pressure, determine clinical significance, and elucidate biological mechanisms underlying this association.
Topics: Adult; Blood Pressure; Chlorpyrifos; Humans; Hypertension; Insecticides; Nitrophenols; Nutrition Surveys; Organophosphorus Compounds
PubMed: 35934697
DOI: 10.1186/s12940-022-00887-3 -
Current Opinion in Structural Biology Aug 2021The evolution of novel enzymes has fueled the diversification of life on earth for billions of years. Insights into events that set the stage for the evolution of a new... (Review)
Review
The evolution of novel enzymes has fueled the diversification of life on earth for billions of years. Insights into events that set the stage for the evolution of a new enzyme can be obtained from ancestral reconstruction and laboratory evolution. Ancestral reconstruction can reveal the emergence of a promiscuous activity in a pre-existing protein and the impact of subsequent mutations that enhance a new activity. Laboratory evolution provides a more holistic view by revealing mutations elsewhere in the genome that indirectly enhance the level of a newly important enzymatic activity. This review will highlight recent studies that probe the early stages of the evolution of a new enzyme from these complementary points of view.
Topics: Evolution, Molecular; Mutation; Proteins
PubMed: 33865035
DOI: 10.1016/j.sbi.2021.03.001