User:Amped4chem/Clastogen

Proposed Edits

Wikipedia Draft - Clastogens

Proposed Edits:

I. Add to the explanation of what a clastogen is:

What are clastogens?

• The preferential breaking of chromosomes at specific sites, called hot-spots, may be involved in acquired disorders, and the topological similarities between fragile sites and oncogene sites have generated interest. B. Dutrillaux reports in the following pages radiation-induced rearrangements, and extensive work has shown that non-random distribution is related to chromosome size and structure.

Extensive studies have been conducted to correlate chromosome mutations and carcinogenic processes, and it appears more evident that chromosome breaks are not the only mechanisms involved in carcinogenesis and that abnormal mitotic processes raising aneuploid cells are also involved in the carcinogenic transformation of cells. Indeed, the in vivo mouse bone-marrow micronucleus test has been used to detect both clastogens and aneuploidogens, since it has been demonstrated that the size of micronuclei and their kinetics of appearance are good criteria for differentiating between clastogens and aneuploidogens. 4

What is the difference between the Clastogenic and Aneugenic potentials?

• Aneugens cause genomic instability with numerical aberration of chromosomes via DNA replication stresses. Clastogens cause structural aberrations of chromosomes, which potentially trigger mutations via repairing errors.

Examples of clastogens. And examples of common products/places they are encountered.

II. Changes to Section “Impact and DNA” :

• This section currently lists findings from 3 different articles with very little context, explanation, or link
• Most important section in need of clarification
• Expand on mechanisms of DNA damage (possibly link to related articles)
• Link or explain “micronuclei” as an important topic related to clastogenic activity
• Explain caffeine clastogen designation
• Example of an image for mechanisms

• Expand How they affect DNA

III.Changes to Section “Assays” :

Discuss or link different assays and why they are used

Improve “flow” of scientific communication (comes across disjointed or disorganized)

Move some of micronucleus discussion into Impact and DNA

A. Identification methods

Assays have been developed in fungi, where chromosome and spindle organization is similar to that in higher eukaryotic cells. This method is able to detect non-clastogenic, carcinogenic compounds (diethylstilboestrol) and, for that reason, is seen as potentially useful in screening test batteries. Indeed, the method involving the counting of chromosomes per metaphase has been used by several workers and is currently considered to be one of the best validated methods in that field. J. Parry presents results of testing cigarette-smoke condensate using either yeast or a Chinese hamster cell line, as well as some structure–toxicity relationship data for benzodiazepines and stilboestrol analogues and some correlations between aneuploidy and carcinogenicity.

But assays are time-consuming so novel methods for monitoring clastogens and aneuploidogens (spindle inhibitors) are highly desirable

use of the monochromosomal hybrid cell for the detection of mis-segregating chromosomes.

A session on flow cytometry generated interest in the use of this technique in genetic toxicology.

The detection of micronuclei and hypodiploidy in CHO-K1 cells by flow cytometry has been proposed as a screening tool for the detection of clastogens as well as aneuploidogens...

IV. Changes to Sections “Telomeres” and “In Rats”:

Not sure these need their own sections

• Telomeres should be discussed during Impact on DNA
• In Rats is one article major result discussing a new potential clastogen
• In Rats finding could be incorporated into Impact on DNA or rolled into a new section about new potential clastogens or clastogenic activity studies in mammalian systems

Our In Progress and Potential References:

1. “Aneugen Versus Clastogen Evaluation and Oxidative Stress-Related Mode-of-Action Assessment of Genotoxic Compounds Using the ToxTracker Reporter Assay” by Inger Brandsma , Nynke Moelijker, Remco Derr , and Giel Hendriks

doi: 10.1093/toxsci/kfaa103

2. “Potent Clastogenicity of Bisphenol Compounds in Mammalian CellsHuman CYP1A1 Being a Major Activating Enzyme” by Hang Yu, Zhihong Chen, Keqi Hu, Zongying Yang, Meiqi Song, Zihuan Li, and Yungang Liu

https://doi-org.proxy.lib.umich.edu/10.1021/acs.est.0c04808

3. Not an article but a collection of articles/books/reviews through ScienceDirect that could all be useful : https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/clastogen

4. “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.”

https://doi.org/10.1016/j.mrrev.2008.11.004

https://www.sciencedirect.com/science/article/pii/B9780123881762500229

Tenchini et al., 1983

M.L. Tenchini, A. Mottura, M. Velicogna, M. Pessina, G. Rainaldi, L. de Carli

Mutation Res., 121 (1983), pp. 139-146

DOI:10.1016/j.mrrev.2008.11.004

https://www.bioscience.org/2017/v9s/af/468/2.htm

First Draft

A clastogen is a mutagenic agents that disturbs normal DNA related processes or directly causes DNA strand breakages, thus causing the deletion, insertion, or rearrangement of entire chromosome sections. These processes are a form of mutagenesis which if left unrepaired, or improperly repaired, can lead to cancer. Known clastogens include acridine yellow, benzene, ethylene oxide, arsenic, phosphine, mimosine, actinomycin D, camptothecin, methotrexate, methyl acrylate, resorcinol and 5-fluorodeoxyuridine. Additionally, 1,2-dimethylhydrazine is a known colon carcinogen and shows signs of possessing clastogenic activity. 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 types, such as caffeine which exhibits clastogenic activity in plant cells. Researchers are interested in clastogens for researching cancer, as well as for other human health concerns such as the inheritability of clastogen effected paternal germ cells that lead to fetus developmental defects.

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.

How Clastogens Cause DNA damage

There is not one all encompassing method by which clastogens damage chromosomal DNA, instead different clastogens have unique ways they interact with DNA, or DNA associated proteins, 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. 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. DNA is frequently damaged and there are many DNA repair pathways that combat this, but repair does not always work perfectly resulting in mistakes (called a misrepair). A widely studied class of clastogens are alkylating agents which do not break DNA at all, but instead form DNA adducts, and these have often eluded the common theories for DNA breaks leading to misrepair. The final theory encompasses clastogens that do not interact with DNA but instead impair DNA synthesis proteins or DNA repair proteins causing damage to occur through loss of normal function of the protein.

Clastogen damage in certain areas of the chromosome can lead to instability, such as loss or damage to telomeres. 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.

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 / Mutation Research 681 (2009) 271–298273. : Mar-Jun 2009;681(2-3):271-298. doi: 10.1016/j.mrrev.2008.11.004.

Methods for Studying Clastogens

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 to screen for clastogens.

The micronucleus test is another type of assay that uses gut cells to observe clastogens, and there are a few different types. The micronucleus test on gut cells is useful because in the case of the bone marrow 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 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 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.

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.

In plants and mice cells studies have found that purine receptor agonists adenosine, ATP, ADP, cyclohexyladenosine, phenylisopropyladenosine and dimethylaminopurine riboside can lower the amount of clastogen damage seen in chromosomes and reduce the amount of micronuclei affected brought on by ethylmethane sulfonate and cyclophosphamide. Some ligands more than others can stop or reduce the clastogen activity of ethylmethane sulfonate such as adenosine, ADP or DAP.

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.