API

Stressor: 43

Title

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Organophosphates

Stressor Overview

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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User term DTXID Preferred name Casrn jchem_inchi_key indigo_inchi_key
parathion DTXSID7021100 Parathion 56-38-2 LCCNCVORNKJIRZ-UHFFFAOYSA-N LCCNCVORNKJIRZ-UHFFFAOYSA-N
Pinacolyl methylfluorophosphonate DTXSID2031906 Pinacolyl methylphosphonofluoridate 96-64-0 GRXKLBBBQUKJJZ-UHFFFAOYNA-N GRXKLBBBQUKJJZ-UHFFFAOYSA-N

AOP Evidence

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Event Evidence

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Acetylcholinesterase (AchE) Inhibition

The MIE, AChE inhibition, is triggered via electrostatic interaction at the anionic site of the enzyme and binding with the serine hydroxyl group at the esteratic site of AChE (Wilson 2010; Fukuto 1990).  Organophosphate pesticides attach to the AChE via an ‘irreversible’ phosphorylation of the enzyme. Note that the use of the term ‘irreversible’ relates to the relative rate at which the phosphorylation occurs since acetylcholine and organophosphates both form covalent bonds with the enzyme. The phosphorylated form may persist for up to a week if it has undergone an ‘aging’ process; i.e., the organophosphate has undergone a dealkylation, thereby strengthening the bond between the OP and the enzyme (Mileson et al. 1998; Kropp and Richardson 2003; Sogob and Vilanova 2002).  Certain steric and electronic requirements must be met in order for an organophosphate to inhibit AChE. For instance, organophosphates require a leaving group sufficiently electronegative to ensure the formation of a reactive electrophile (Fukuto 1990; Sogob and Vilanova 2002; Schűűrmann 1992). Substances with subtle structural differences can result in major changes in AChE inhibition capabilities.  For example, OPs having identical R and R1 alkyl groups display decreasing AChE inhibition as the R / R1 carbon chain increases from a single carbon to a propyl moiety, with the latter resulting in an ineffective AChE inhibitor (Fukuto 1999).  

Metabolism also plays an important role in the potency of organophosphates.  For instance, organophosphates in the phosphorothionate and phosphorodithioate families (i.e., P=S) must undergo metabolic activation, via cytochrome P450-based monoxygenases, to an oxon form in order to inhibit AChE effectively (Fukuto 1990). 

 

Base Structure (OP)

Configuration

R: A simple alkyl (e.g., methyl or ethyl group) or aryl group bonded to either an oxygen or sulfur that is directly bonded to the phosphorous; 

R1:  Methoxy, ethoxy, ethyl, phenyl, amino, substituted amino, or alkylthio group;

X:  Leaving group that is or contains an electronegative moiety (e.g., phenoxy or aromatic group containing hetero atoms, substituted thioalkyl, or substituted alkoxy groups);

O: Oxons are direct acting

S: Thiophosphates require metabolic activation to the oxon form in order to be active AChE inhibitors

 

Evidence exists that immature life stages in mammals and birds may be more sensitive to organophosphate pesticides (see Grue et al., 1997; Grue et al., 1983; Grue et.al; 1981). It has been suggested that this may be related to the amount of pesticide ingested in relation to body size (Ludke et al, 1975), but there is direct data in rats showing that differential sensitivity to OPs is determined at least in part by inadequate detoxification in the young (Moser, 2011). OP detoxification is highly dependent on enzymes such as A-esterases (paraoxonases, PON) and carboxylesterases (e.g., Benke and Murphy, 1974; Furlong, 2007; Sterri et al., 1985; Vilanova and Sogorb, 1999), which are present at lower levels in the young (e.g., Chanda et al., 2002; Mendoza, 1976; Mortensen et al., 1996; Moser et al., 1998).




Stressor Info

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Chemical/Category Description

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Organophosphate



Characterization of Exposure

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repeated exposure



References

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Collombet JM, Four E, Fauquette W, Burckhart MF, Masqueliez C, Bernabe D, Baubichon D, Lallement G (2007) Soman poisoning induces delayed astrogliotic scar and angiogenesis in damaged mouse brain areas. Neurotoxicology 28: 38-48

Zurich MG, Honegger P, Schilter B, Costa LG, Monnet-Tschudi F (2004) Involvement of glial cells in the neurotoxicity of parathion and chlorpyrifos. Toxicol Appl Pharmacol 201: 97-104