Organophosphorous Pesticides - Mechanisms of Their Toxicity

Eleršek, Tina; Filipič, Metka

doi:10.5772/14020

Cited by 50 publications

(39 citation statements)

References 40 publications

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“…Inhibition of AChE, which catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh), results in increased levels of synaptic ACh and subsequent overstimulation of nicotinic and muscarinic ACh receptors. Cholinergic toxicity is clinically manifested by decreased heart and respiration rates, increased secretions (sweating, lacrimation, and salivation), muscle tremors, and eventually paralysis and death (Eleršek and Filipic 2011; Russom et al 2014; King and Aaron 2015; Taylor 2017). Because of its key role in regulating cognitive, peripheral autonomic, and somatic motor functions, AChE is also a common pharmacological target.…”

Section: Introductionmentioning

confidence: 99%

Planarian cholinesterase: molecular and functional characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity

Hagstrom

Zhang

et al. 2017

Arch Toxicol

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The asexual freshwater planarian Dugesia japonica has emerged as a medium-throughput alternative animal model for neurotoxicology. We have previously shown that D. japonica are sensitive to organophosphorus pesticides (OPs) and characterized the in vitro inhibition profile of planarian cholinesterase (DjChE) activity using irreversible and reversible inhibitors. We found that DjChE has intermediate features of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Here, we identify two candidate genes (Djche1 and Djche2) responsible for DjChE activity. Sequence alignment and structural homology modeling with representative vertebrate AChE and BChE sequences confirmed our structural predictions, and show that both DjChE enzymes have intermediate sized catalytic gorges and disrupted peripheral binding sites. Djche1 and Djche2 were both expressed in the planarian nervous system, as anticipated from previous activity staining, but with distinct expression profiles. To dissect how DjChE inhibition affects planarian behavior, we acutely inhibited DjChE activity by exposing animals to either an OP (diazinon) or carbamate (physostigmine) at 1 µM for 4 days. Both inhibitors delayed the reaction of planarians to heat stress. Simultaneous knockdown of both Djche genes by RNAi similarly resulted in a delayed heat stress response. Furthermore, chemical inhibition of DjChE activity increased the worms' ability to adhere to a substrate. However, increased substrate adhesion was not observed in Djche1/Djche2 (RNAi) animals or in inhibitor-treated day 11 regenerates, suggesting this phenotype may be modulated by other mechanisms besides ChE inhibition. Together, our study characterizes DjChE expression and function, providing the basis for future studies in this system to dissect alternative mechanisms of OP toxicity.

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Section: Introductionmentioning

confidence: 99%

Planarian cholinesterase: molecular and functional characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity

Hagstrom

Zhang

et al. 2017

Arch Toxicol

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“…With respect to the OPs, less is known about OP effects on other target organs such as the testis. Because spermatogenesis is a highly complex process dependent upon optimal conditions to occur correctly (Cheng and Mruk, 2009, 2010), OP secondary mechanisms that are not associated with the cholinergic system, including inhibitory mechanisms of androgenic activity mediated by hormones, may lead to endocrine disrupting effects (Elersek and Filipic, 2011; Kang et al, 2004). …”

Section: Discussionmentioning

confidence: 99%

Dialkyl phosphate urinary metabolites and chromosomal abnormalities in human sperm

Figueroa

Young

Meeker

et al. 2015

Environmental Research

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Background The past decade has seen numerous human health studies seeking to characterize the impacts of environmental exposures, such as organophosphate (OP) insecticides, on male reproduction. Despite an extensive literature on OP toxicology, many hormone-mediated effects on the testes are not well understood. Objectives This study investigated environmental exposures to OPs and their association with the frequency of sperm chromosomal abnormalities (i.e., disomy) among adult men. Methods Men (n=159) from a study assessing the impact of environmental exposures on male reproductive health were included in this investigation. Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total disomy in sperm nuclei. Urine was analyzed using gas chromatography coupled with mass spectrometry for concentrations of dialkyl phosphate (DAP) metabolites of OPs [dimethylphosphate (DMP); dimethylthiophosphate (DMTP); dimethyldithiophosphate (DMDTP); diethylphosphate (DEP); diethylthiophosphate (DETP); and diethyldithiophosphate (DEDTP)]. Poisson regression was used to model the association between OP exposures and disomy measures. Incidence rate ratios (IRRs) were calculated for each disomy type by exposure quartiles for most metabolites, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. Results A significant positive trend was seen for increasing IRRs by exposure quartiles of DMTP, DMDTP, DEP and DETP in XX18, YY18, XY18 and total disomy. A significant inverse association was observed between DMP and total disomy. Findings for total sum of DAP metabolites concealed individual associations as those results differed from the patterns observed for each individual metabolite. Dose-response relationships appeared nonmonotonic, with most of the increase in disomy rates occurring between the second and third exposure quartiles and without additional increases between the third and fourth exposure quartiles. Conclusions This is the first epidemiologic study of this size to examine the relationship between environmental OP exposures and human sperm disomy outcomes. Our findings suggest that increased disomy rates were associated with specific DAP metabolites, suggesting that the impacts of OPs on testis function need further characterization in epidemiologic studies.

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“…AChE is found in the synaptic membrane where it degrade the hydrolytic activity of the neurotransmitter acetylcholine, producing choline and acetate, a reaction important for the regulation of synaptic activity in central and peripheral neural system. 21 AChE plays a significant role in nerve conduction process at myoneutral junction of nerve ending of muscle tissue. 22 AChE inhibition caused accumulation of acetylcholine at the that inhibition of ACP by column purified fraction of T. indica seed and procynadine was competitive (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition Kinetics of Acetylcholinesterase and Phosphatases by the Active Constituents of Terminalia arjuna and Tamarindus indica in the Cerebral Ganglion of Lymnaea acuminata

Soni¹,

Singh²,

Singh³

2017

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Introduction: Paper demonstrates effect of the active molluscicidal components arjunolic acid (Terminalia arjuna bark) and procynadine (Tamarindus indica seed) on the activity of acetylcholinesterase (AChE) and phosphatases (ACP/ALP) in the cerebral ganglion of snail Lymnaea acuminata. Materials and Methods: Kinetics of AChE/ACP/ ALP inhibition in the cerebral ganglion of snail Lymnaea acuminata was studied via in vivo (40% and 80% of 96 h LC 50 ) and in vitro treatments (0.3 µg to 7.0 µg) of the column purified fractions, arjunolic acid and procynadine. Results: In vivo exposure of procynadine and arjunolic acid significantly inhibit acetylcholinesterase (AChE), acid phosphatase (ACP) and alkaline phosphatase (ALP) activities in the cerebral ganglion of L. acuminata exposed to 80% of 96h LC 50 . In in vitro treatment maximum inhibition in AChE/ACP/ALP activities in the cerebral ganglion of snail were noted when exposed to 7.0 µg of arjunolic acid and 0.9 µg of procynadine. Column purified fraction of T. arjuna bark and T. indica seed caused non-competitive and uncompetitive inhibition of AChE activity, respectively. Column purified fraction and arjunolic acid of T. arjuna bark caused uncompetitive inhibition of ACP while column purified fraction and procynadine of T. indica seed caused competitive inhibition. Competitivenon-competitive inhibition of ALP activity in the cerebral ganglion of L. acuminata was observed after treatment of column purified active components of both plants. Conclusions: The molluscicidal activity of T. arjuna bark (arjunolic acid) and T. indica seed (procynadine) against snail L. acuminata is due to the inhibition of AChE/ACP/ ALP. Their inhibition kinetics against AChE/ACP/ALP, were different in cerebral ganglion of snail.

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Organophosphorous Pesticides - Mechanisms of Their Toxicity

Cited by 50 publications

References 40 publications

Planarian cholinesterase: molecular and functional characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity

Planarian cholinesterase: molecular and functional characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity

Dialkyl phosphate urinary metabolites and chromosomal abnormalities in human sperm

Inhibition Kinetics of Acetylcholinesterase and Phosphatases by the Active Constituents of Terminalia arjuna and Tamarindus indica in the Cerebral Ganglion of Lymnaea acuminata

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