# Clastogen

> Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Clastogen
> Markdown URL: https://mediated.wiki/source/Clastogen.md
> Source: https://en.wikipedia.org/wiki/Clastogen
> Source revision: 1348570557
> License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/)

{{short description|Substance that can cause breaks in chromosomes}}
{{main| mutagenic  }}
thumb|Figure comparing the effects of exposure to genotoxic agents (aneugens and clastogens) on DNA. Aneugens induce mis-segregation of chromosomes into daughter cells while clastogens break the DNA and chromosome.
A '''clastogen''' is a [mutagen](/source/mutagen)ic agent that disturbs normal [DNA](/source/DNA) related processes or directly causes [DNA](/source/DNA) strand breakages, thus causing the [deletion](/source/Deletion_(genetics)), [insertion](/source/Insertion_(genetics)), or rearrangement of entire [chromosome](/source/chromosome) sections.<ref name="Schwab_2011">{{cite book|title=Encyclopedia of Cancer|date=2011|publisher=Springer Berlin Heidelberg|isbn=978-3-642-16482-8 |veditors=Schwab M |place=Berlin, Heidelberg |pages=879|language=en|chapter=Clastogen|doi=10.1007/978-3-642-16483-5_1205}}</ref> These processes are a form of [mutagenesis](/source/mutagenesis) which if left unrepaired, or improperly repaired, can lead to [cancer](/source/cancer).<ref name="Schwab_2011" /> Known clastogens include [acridine yellow](/source/acridine_yellow), [benzene](/source/benzene), [ethylene oxide](/source/ethylene_oxide), [arsenic](/source/arsenic), [phosphine](/source/phosphine), [mimosine](/source/mimosine), [actinomycin D](/source/Dactinomycin), [camptothecin](/source/camptothecin), [methotrexate](/source/methotrexate), [methyl acrylate](/source/methyl_acrylate), [resorcinol](/source/resorcinol) and [5-fluorodeoxyuridine](/source/Floxuridine).<ref name="Kirpnick_2005">{{cite journal | vauthors = Kirpnick Z, Homiski M, Rubitski E, Repnevskaya M, Howlett N, Aubrecht J, Schiestl RH | title = Yeast DEL assay detects clastogens | journal = Mutation Research | volume = 582 | issue = 1–2 | pages = 116–134 | date = April 2005 | pmid = 15781217 | doi = 10.1016/j.mrgentox.2005.01.005 | bibcode = 2005MRGTE.582..116K }}</ref> Additionally, [1,2-dimethylhydrazine](/source/1%2C2-dimethylhydrazine) is a known colon [carcinogen](/source/carcinogen) and shows signs of possessing clastogenic activity.<ref name="Vanhauwaert_2001">{{cite journal | vauthors = Vanhauwaert A, Vanparys P, Kirsch-Volders M | title = The in vivo gut micronucleus test detects clastogens and aneugens given by gavage | journal = Mutagenesis | volume = 16 | issue = 1 | pages = 39–50 | date = January 2001 | pmid = 11139597 | doi = 10.1093/mutage/16.1.39 | doi-access = free }}</ref> There are many clastogens not listed here and research is ongoing to discover new clastogens. Some known clastogens only exhibit clastogenic activity in certain [cell](/source/Cell_(biology)) types, such as caffeine which exhibits clastogenic activity in plant cells.<ref name="Bignold_2009">{{cite journal | vauthors = Bignold LP | title = Mechanisms of clastogen-induced chromosomal aberrations: a critical review and description of a model based on failures of tethering of DNA strand ends to strand-breaking enzymes | journal = Mutation Research | volume = 681 | issue = 2–3 | pages = 271–298 | date = March–June 2009 | pmid = 19103303 | doi = 10.1016/j.mrrev.2008.11.004 | bibcode = 2009MRRMR.681..271B }}</ref> Researchers are interested in clastogens for researching [cancer](/source/cancer), as well as for other human health concerns such as the inheritability of clastogen effected paternal [germ cell](/source/germ_cell)s that lead to [fetus](/source/fetus) developmental defects.<ref name="Wyrobek_2005">{{cite journal | vauthors = Wyrobek AJ, Schmid TE, Marchetti F | title = Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies | journal = Journal of the National Cancer Institute. Monographs | volume = 2005 | issue = 34 | pages = 31–35 | date = 2005-03-01 | pmid = 15784819 | doi = 10.1093/jncimonographs/lgi001 | doi-access = free }}</ref>

== Mechanism ==
thumb|Summary of theories of the mechanisms of chromosomal aberrations: A, ‘classic’ breaks theory; B, ‘mis-repair of breaks’ theory; C, ‘repair-created breaks’ theory. Adapted from Bignold.<ref name = "Bignold_2009" />
There is not one all encompassing method by which clastogens damage chromosomal [DNA](/source/DNA), instead different clastogens have unique ways they interact with DNA, or DNA associated [protein](/source/protein)s, and disrupt normal function. Broadly these different types of clastogenic activity can be organized into three classes: ‘classic’ breaks theory; ‘mis-repair of breaks’ theory and ‘repair-created breaks’ theory.<ref name = "Bignold_2009" /> It may not always be known how a clastogen causes chromosomal damage.

Radiation was the earliest known clastogen that caused direct DNA damage, following the classic breaks theory.<ref>{{cite journal | vauthors = Sax K | title = An Analysis of X-Ray Induced Chromosomal Aberrations in Tradescantia | journal = Genetics | volume = 25 | issue = 1 | pages = 41–68 | date = January 1940 | pmid = 17246957 | pmc = 1209078 | doi = 10.1093/genetics/25.1.41 }}</ref> DNA is frequently damaged and there are many [DNA repair](/source/DNA_repair) pathways that combat this, but repair does not always work perfectly resulting in mistakes (called a misrepair).<ref>{{cite journal | vauthors = Rothkamm K, Löbrich M | title = Misrepair of radiation-induced DNA double-strand breaks and its relevance for tumorigenesis and cancer treatment (review) | journal = International Journal of Oncology | volume = 21 | issue = 2 | pages = 433–440 | date = August 2002 | pmid = 12118342 }}</ref> A widely studied class of clastogens are [alkylating](/source/Alkylation) agents which do not break DNA at all, but instead form [DNA adduct](/source/DNA_adduct)s, and these have often eluded the common theories for DNA breaks leading to misrepair.<ref name="Bignold_2009" /> The final theory encompasses clastogens that do not interact with DNA but instead impair [DNA synthesis](/source/DNA_synthesis) [protein](/source/protein)s or [DNA repair](/source/DNA_repair) [protein](/source/protein)s causing damage to occur through loss of normal function of the protein.<ref name="Bignold_2009" />

Clastogen damage in certain areas of the [chromosome](/source/chromosome) can lead to instability, such as loss or damage to [telomere](/source/telomere)s.<ref name="Bolzán_2020">{{cite journal | vauthors = Bolzán AD | title = Using telomeric chromosomal aberrations to evaluate clastogen-induced genomic instability in mammalian cells | journal = Chromosome Research | volume = 28 | issue = 3–4 | pages = 259–276 | date = December 2020 | pmid = 32940874 | doi = 10.1007/s10577-020-09641-2 | s2cid = 221768891 | hdl = 11336/154072 | hdl-access = free }}</ref> Studies have shown that rat cells that were exposed to chemical clastogens express telomeric irregularities in function and can remain for several cell generations after treatment has been attempted.<ref name="Bolzán_2020" />

== Detection ==
There are many different methods for testing for clastogenic activity. Two of the most common methods are listed below, but this is not a comprehensive guide.

There have been studies done that work with the usage of the deletion (DEL) [assay](/source/assay) to screen for clastogens.

The micronucleus test is another type of [assay](/source/assay) that uses gut cells to observe clastogens, and there are a few different types. The [micronucleus](/source/micronucleus) test on gut cells is useful because in the case of the bone marrow [micronucleus](/source/micronucleus) test there is not much activity seen after there has been oral exposure therefore more activity is seen in the gut cells. [In vitro](/source/In_vitro) [micronucleus](/source/micronucleus) assay (IVMN) can screen for clastogen activity, this method is useful because it can pick up clastogen activity and be used to foresee [chromosome aberration](/source/Chromosome_abnormality) activity. The IVMN assay can pick up on fragments that were membrane bound to DNA that were split from nuclei throughout the process of cell division.

These assays are time-consuming so novel methods for monitoring clastogens and aneuploidogens are highly desirable. One example is the use of the monochromosomal hybrid cell for the detection of mis-segregating chromosomes.

== Telomeres ==
There is a possibility of clastogens affecting telomeres. There can be uncertainty with telomeres that occur short term during the first round of cell division in which there can be chromosomal damage by clastogens. Clastogens (which break chromosomes) contribute to telomeric instability because it leads to chromosome end loss or true telomere loss. Clastogens can bring on issues with telomeres and cause them to fail to function as intended, most often seen anomalies are seen to occur in human lymphocytes, cancer cell lines, and non-human established cell lines where there is telomere loss and copies of anomalies in the exposed cells, thus, the problems that arise in telomeres can be duplicated and seen in exposed cells.

In addition, studies have shown that rat cells that were exposed to chemical clastogens express telomeric irregularities in function and can remain for several cell generations after treatment has been attempted.<ref name="Bolzán_2020" />

== Research ==
In terms of resistance, for a specific clastogen known as "Zeocin", an amino acid residue known as XLF-L115D mutant is flawed in terms of being resistant thus the clastogen activity shows no amount of decreasing.<ref name="Bhargava_2020">{{cite journal | vauthors = Bhargava R, Lopezcolorado FW, Tsai LJ, Stark JM | title = The canonical non-homologous end joining factor XLF promotes chromosomal deletion rearrangements in human cells | journal = The Journal of Biological Chemistry | volume = 295 | issue = 1 | pages = 125–137 | date = January 2020 | pmid = 31753920 | pmc = 6952595 | doi = 10.1074/jbc.RA119.010421 | doi-access = free }}</ref>

In plants and mice cells studies have found that [purine](/source/purine) [receptor](/source/Receptor_(biochemistry)) [agonist](/source/agonist)s [adenosine](/source/adenosine), [ATP](/source/Adenosine_triphosphate), [ADP](/source/Adenosine_diphosphate), [cyclohexyladenosine](/source/cyclohexyladenosine), phenylisopropyladenosine and dimethylaminopurine riboside can lower the amount of clastogen damage seen in [chromosome](/source/chromosome)s and reduce the amount of [micronuclei](/source/Micronucleus) affected brought on by [ethyl methanesulfonate](/source/ethyl_methanesulfonate) and [cyclophosphamide](/source/cyclophosphamide). Some [ligand](/source/ligand)s more than others can stop or reduce the clastogen activity of ethyl methanesulfonate such as [adenosine](/source/adenosine), [ADP](/source/Adenosine_diphosphate) or DAP.<ref name="Kharitonov_2001">{{cite journal | vauthors = Kharitonov VS, Semenov VV, Barabanshchikov BI | title = Purine receptor agonists protect the genome of plant and animal cells from clastogen damage | journal = Bulletin of Experimental Biology and Medicine | volume = 132 | issue = 1 | pages = 666–669 | date = July 2001 | pmid = 11687849 | doi = 10.1023/a:1012580328826 | s2cid = 19132027 }}</ref>

In a study where rats were treated with Brevetoxin B (PbTx2), there was a noticeable 2-3 fold growth in the amount of DNA seen in comet tails which tell us that Brevetoxin B shows in vivo clastogenic activity. This clastogen activity was seen after Brevetoxin B was injected by way of intratracheal administering in the rat.<ref name="Leighfield_2009">{{cite journal | vauthors = Leighfield TA, Muha N, Ramsdell JS | title = Brevetoxin B is a clastogen in rats, but lacks mutagenic potential in the SP-98/100 Ames test | journal = Toxicon | volume = 54 | issue = 6 | pages = 851–856 | date = November 2009 | pmid = 19559041 | doi = 10.1016/j.toxicon.2009.06.018 | bibcode = 2009Txcn...54..851L }}</ref>

== References ==
{{reflist}}

{{Genotoxicity}}

Category:Mutation

---
Adapted from the Wikipedia article [Clastogen](https://en.wikipedia.org/wiki/Clastogen) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Clastogen?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.