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Environmental Health Perspectives Apr 2021Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used...
BACKGROUND
Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).
OBJECTIVES
The objective of the current study was to identify environmental chemicals that inhibit AChE activity using and models.
METHODS
To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.
RESULTS
A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.
CONCLUSIONS
Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Humans; Insecticides; Molecular Docking Simulation
PubMed: 33844597
DOI: 10.1289/EHP6993 -
The Science of the Total Environment Feb 2024Widespread use of pesticides globally has led to serious concerns about environmental contamination, particularly with regard to aquatic and soil ecosystems. This work...
Widespread use of pesticides globally has led to serious concerns about environmental contamination, particularly with regard to aquatic and soil ecosystems. This work involved investigating concentrations of 64 pesticides in surface-water and soil samples collected in four provinces along the Mekong River in Cambodia during the dry and rainy seasons (276 samples in total), and conducting semi-structured interviews with local farmers about pesticide use. Furthermore, an ecological risk assessment of the detected pesticides was performed. In total, 56 pesticides were detected in surface water and 43 in soil, with individual pesticides reaching maximum concentrations of 1300 ng/L in the surface-water samples (tebufenozide) and 1100 ng/g dry weight in the soil samples (bromophos-ethyl). The semi-structured interviews made it quite evident that the instructions that farmers are provided regarding the use of pesticides are rudimentary, and that overuse is common. The perceived effect of pesticides was seen as an end-point, and there was a limited process of optimally matching pesticides to pests and crops. Several pesticides were used regularly on the same crop, and the period between application and harvest varied. Risk analysis showed that bromophos-ethyl, dichlorvos, and iprobenfos presented a very high risk to aquatic organisms in both the dry and rainy seasons, with risk quotient values of 850 for both seasons, and of 67 in the dry season and 78 in the rainy season for bromophos-ethyl, and 49 in the dry season and 16 in the rainy season for dichlorvos. Overall, this work highlights the occurrence of pesticide residues in surface water and soil along the Mekong River in Cambodia, and emphasizes the urgent need for monitoring and improving pesticide practices and regulations in the region.
Topics: Rivers; Water; Soil; Dichlorvos; Cambodia; Ecosystem; Environmental Monitoring; Water Pollutants, Chemical; Pesticides; Pesticide Residues; Organothiophosphates
PubMed: 38104830
DOI: 10.1016/j.scitotenv.2023.169312 -
Saudi Journal of Biological Sciences Jan 2021larvae obtained from different types of agricultural and non-agricultural localities in Peninsular Malaysia were subjected to several larvicides at World Health...
larvae obtained from different types of agricultural and non-agricultural localities in Peninsular Malaysia were subjected to several larvicides at World Health Organization (WHO) recommended dosages. Upon 24 h of WHO larval bioassay using two organochlorines and six organophosphates, high resistance against dichlorodiphenyltrichloroethane (DDT), temephos, chlorpyrifos and bromophos were demonstrated among all larval populations. larvae from both paddy growing areas (92.33% mortality) and rubber estates (97.00% mortality) were moderately resistant to dieldrin while only larvae from dengue prone residential areas (89.00% mortality) showed high resistance against dieldrin. All larval populations also developed either incipient or high resistance to both malathion (33.67%-95.33% mortality) and fenitrothion (73.00%-92.67% mortality). Only larvae from fogging-free residential areas that were tolerant to fenthion (97.33% mortality), whereas larvae from dengue prone residential areas were highly resistant to the same organophosphate (88.33% mortality). Cross resistance between intraclass and interclass larvicides of organochlorines and organophosphates were also exhibited in this study. The present study provided baseline data on various susceptibility levels of larval populations from different types of agricultural and non-agricultural localities against organochlorines and organophosphates at WHO recommended dosages. Nevertheless, further susceptibility investigations are suggested using revised doses of larvicides established from the local reference strain of to prevent the underestimation or overestimation of insecticide resistance level among field strains of larvae.
PubMed: 33424394
DOI: 10.1016/j.sjbs.2020.11.040