API

Stressor: 124

Title

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Colchicine

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
Colchicine DTXSID5024845 Colchicine 64-86-8 IAKHMKGGTNLKSZ-INIZCTEOSA-N IAKHMKGGTNLKSZ-INIZCTEOSA-N

AOP Evidence

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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

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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

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Chemical/Category Description

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Characterization of Exposure

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References

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