Stressor: 124

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

Colchicine

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
Colchicine DTXSID5024845 Colchicine 64-86-8 IAKHMKGGTNLKSZ-INIZCTEOSA-N IAKHMKGGTNLKSZ-INIZCTEOSA-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
Chemical binding to tubulin in oocytes leading to aneuploid offspring

This is the prototype agent for binding to tubulin.

Colchicine binds at a site on tublulin known as the colchicine binding domain, which is a deep pocket located at the α/β interface of tubulin heterodimers. Both the A and C rings of colchicine are necessary for high affinity binding, while the B ring may only function as a linker between the other two. Three methoxy residues are present in the A ring and all of them are involved in the high affinity binding to tubulin. The C ring of colchicine interacts through van der Waals contacts with Valα181, Serα178, and Valβ315. The carbonyl group behaves as a hydrogen bond acceptor, interacting with Val181a. The A ring is buried in a hydrophobic pocket delimited by Lysβ352, Asnβ350, Leuβ378, Alaβ316, Leuβ255, Lysβ254, Alaβ250, and Leuβ242, and the methoxy group at position 3 is involved in a hydrogen bond interaction within the thiol group of Cysβ241 [Marchetti et al., 2016].

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
Binding, Tubulin

There is no evidence text for this event.

Disruption, Microtubule dynamics

Colchicine interferes with microtubule dynamics at lower concentrations while it induces a net depolymerization at higher concentrations which is a consequence of the inability of further extending the microtubules [Stanton et al., 2011]. This dual action is in common with other spindle poisons (e.g. vinca derivatives) [Panda et al., 1996]. All microtubule-binding agents alter microtubule dynamics, engaging cell cycle surveillance mechanisms that arrest cell division in metaphase. This mitotic stall may then lead to various irremediable effects such as mitotic catastrophe, apoptosis or aneuploidy [Kops et al., 2005]. 

After addition of colchicine at concentrations of 0.1-3.0 mM, microtubule polymerization decreased rapidly and simultaneously thoughout the central spindle and aster (Salmon et al, 1984)

Disorganization, Spindle

In vitro treatment with 0.4 micrograms/mL (1 microM) induces reduction of spindle size and lowe microtubule density; cytoskeleton remodeling  is also observed (Ibanez et al 2003). In addtion, colchicine treament results in abnormal spindle localization of several proteins that are essential for chormosome segregation, such as: Aurora A (Yao et al 2004); Polo-like-kinase I (Yao et al 2003; Tong et al 2002); GTPase Ran (Cao et al, 2005)

Altered, Chromosome number

Ten fold significant increase of hyperhaploid oocytes. 8.6% (30/342) hyperhaploid oocytes vs 0.8% (14/1730) in controls. Oocytes collected aftern natural ovulation, strenghtening the relevance of data for human hazard  assessment (Sugawara and Mikamo, 1980)

In Djungarian hamsters, 3 mg/kg Colchicine 5 hours after induction of ovulation induces a significant increase of hyperhaploid oocytes. 11.7% (16/137) hyperhaploid oocytes vs 3.5 in controls (Hummler and Hansmann, 1985).

In mice, 0.25 mg/kg Colchicine significantly increased hyperhaploid oocytes in both young and old female (Tease and Fisher, 1986). In another study, 0.2 mg/kg colchicine at diffrent times from the induction of ovulation (-4 hr to +4 hr) significantly increased hyperhaploid oocyte at all timepoint invegated (Mailhes and Yuan, 1987). This study shows that in preovulatory oocytes the sensitivity window for the induction of aneuploidy is at least 8 hr long. In a subsequent study, a dose-related increase in hyperhaploid oocytes was found (Maihes et al 1988). FInally, another study demonstrated that an aneuploidy induction effectiveness ratio of 10 is observed between administering colchicine orally or by intraperiotoneal injection (Mailhes et al 1990)

Increase, Aneuploid offspring

Dose of 2.0, 3.0 and 4.0 mg/kg colchicine administered at the time of the induction of ovulation significantly increased hyperhaploid zygotes over the control values at all doses tested. Comparison with the data obtained in oocytes under the same experimental conditions suppor the notion that aneuploid oocytes can be fertilized and the chromosome defect transmitted to the embryo

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
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

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