Stressor: 43

Title

To create a new stressor, from the Listing Stressors page at https://aopwiki.org/stressors click ‘New stressor.’ This will bring you to a page entitled “New Stressor” where a stressor title can be entered. Click ‘Create stressor’ to create a new Stressor page listing the stressor title at the top. More help

Organophosphates

Stressor Overview

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. More help

AOPs Including This Stressor

This table is automatically generated and lists the AOPs associated with this Stressor. More help

Events Including This Stressor

This table is automatically generated and lists the Key Events associated with this Stressor. More help

Chemical Table

The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as  Preferred name, “CAS- preferred name,” “JChem InChIKey – preferred name,” or “Indigo InChIKey- preferred name,” depending on by which field you perform the search. It may take several moments for the drop down list to display. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.To remove a chemical associated with a particular stressor, in the Chemical Table next to the chemical you wish to delete, click ‘Remove’ and then click 'OK.' The chemical should no longer be visible in the Chemical table. More help
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

This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence term and evidence text from this AOP Stressor. More help

Event Evidence

This table is automatically generated and includes the Events with this associated stressor as well as the evidence text from this Event Stressor. More help
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

Text sections under this subheading include the Chemical/Category Description and Characterization of Exposure. More help
Chemical/Category Description
To edit the Chemical/Category Description” section, on a KER page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “Chemical/Category Description” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “Chemical/Category Description”  section on the page. More help

Organophosphate

Characterization of Exposure
To edit the “Characterization of Exposure” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “Characterization of Exposure”  section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “Characterization of Exposure” section on the page. More help

repeated exposure

References

List of the literature that was cited for this Stressor description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015).To edit the “References” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “References” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “References” section on the page. More help

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