“Mutagen is a physical or chemical agent induces mutation by altering the genetic material, possibly results in the disease condition.”


In a simple language, we can say that the mutagens are the agents that damage our genetic material and results in genetic abnormalities- either inherited or non-inherited. 

The changes that the agents create are called mutations which alters the DNA sequence by inserting, deletion, translocation or inverting the base or base sequences. 

The present topic is very important, in order to understand the mechanism of how genetic mutations are originated in nature. 

Further to this, we will understand how different chemical, physical or biological agents affect our DNA or genetic material by altering the base sequences or the expression of a particular gene. 

The common cause of any mutagen is cancer- uncontrolled growth of cells. 

“A change in the genotype that influence or altered related phenotype is called mutation.”

Insertion, deletion, duplication, translocation, inversion are some of the common types of gene mutations occurs spontaneously in nature while trisomy, monosomy and numerical chromosomal abnormalities are some of the chromosomal abnormalities.

However, not all the mutagens cause mutations, some mutations arise spontaneously due to error in replication, hydrolysis or recombination errors. 

In the present article, we will cover all the information on mutagens and their role in the development of the disease. 

The content of the article is 

  • What are mutagens 
  • Definition of mutagens 
  • Types of mutagens 
    • Physical
      • Radiation
      • Heat
    • Chemical
      • Base analogs
      • Alkylating agents
      • intercalating agents
      • Metal ions
    • biological
      • Viruses
      • bacteria
      • transposons
  • Effect of mutagens 
  • Conclusion

What is mutagen? 

I think it is better to start from the beginning, 

So let’s start from the DNA, 

The DNA is a genetic material- a polynucleotide chain made up of the long chain of A, T, G, and C. Functional piece of a DNA- a gene encodes a specific protein. 

If the sequence of a nucleotide within a gene is changed, the protein can not be formed or an altered protein is formed from it. 

Read more on DNA: DNA story: The structure and function of DNA.

Let’s take an example for that, 

Suppose a gene “DNT” is a 1000 nucleotide long functional gene located on chromosome “Z” (just assume it, it is an example). 

The DNT gene encodes a protein called “doughnut 🍩” which helps in the regulation of cell cycle. Let say, it balances the cell death and cell proliferation. 

If a nucleotide “C” at the position 10 deleted, the protein can not be formed for the DNT gene. Thus the process of cell death and cell proliferation is dis-regulated. 

And this will happen because of the prolonged exposure to UV light. 

The deletion of “C” is called a mutation, the mutation results in cancer and the UV light is called a mutagen. 

From this example, we can say, “due to the mutation delC10 in a gene DNT, a protein ‘doughnut’ can not be formed- results in cancer, which is caused by prolonged exposure of mutagen UV light.”

I think now you understand how mutagens cause mutagens. 

Some of the common mutagens are UV light, X- rays, ROS, Alkalyting agents and base analogs etc. we will discuss each type of agents in the coming section of this article. 

Definition of mutagen: 

“Mutagens are the known agents either physical, chemical or biological causes mutations by altering the genotype or gene expression which results in genetic abnormality.”

In other words, we can say, 

“Mutation causes by any agents is known as a mutagen.”

or

“Natural or artificial agents which change either structure or sequence of a gene or DNA is known as mutagens.”  

Type of mutagens: 

Three different types of common mutagens are observed in nature- physical agents, chemical agents and biological agents. 

Physical agents: 

  • Heat and radiation

Chemical agents 

  • Base analogues 
  • Intercalating agents 
  • Alkylating agents 
  • Deaminating agents 
  • Metal ions 

Biological agents 

  • Viruses 
  • Bacteria 
  • transposons
Classification of mutagens: physical, chemical and biological agents.

Classification of mutagens: physical, chemical and biological agents.

Physical agents: 

Radiation: 

The radiations are the first mutagenic agent reported in 1920. 

UV rays, X-rays, alpha rays, neutrons and other ionizing and non-ionizing radiations are mutagenic. 

The radiation effects at a molecular level by damaging the DNA or nucleotide structure. The damage might be either lethal or sub-lethal. 

(Kill the organism/cell or alter the function of the cell or protein or a gene). 

The electromagnetic radiation is also one of the known mutagens that cause lethal or sub-lethal mutations.  

One of the common type of radion- the iodizing radiation produces the free radicals that damages, not even the DNA but also the protein and lipids present in a cell. 

The rapidly dividing cell types are one of the target types for the ionizing radiations like X-rays, however, the severity of the damage depends on the dose of the radiation. 

The radiation causes cross-linking of DNA or protein, chromosomal break, strand break or loss of chromosomes, also, at the molecular level it causes deletion of bases or DNA strand breakages. 

X-ray radiation: 

The X-rays are one of the most common types of ionizing radiation used in many of the medical practices for various purposes. However, the dose for that is very low. It is even used in the sterilizing practises for destroying microorganism. 

At the molecular level, the lethal dose of X-ray (350-500 rems) breaks the phosphodiester bonds between the DNA and thus results in the strand breakages. 

It causes multiple strand breakage and results in the deletion of the portion of a DNA. If the strand breakage occurs in both the strands, it will become lethal to the cell. 

UV-rays: 

The UV-light is a non-ionizing type of radiation having less energy in it, used in the sterilization and decontamination process during the cell culture and microbiological experiments. 

The UV light is absorbed by the DNA bases as well as protein at 260nm and 280nm, respectively. 

The major causes of UV-radiation are- base deletion, strand breakage, cross-linking and generation of nucleotide dimers. 

The UV-light can be classified into three different categories: 

UV-A: nearly visible range (320nm) causes pyrimidine dimers.

UV-B: (290-320nm) emitted by the sunlight and one of the major mutagen cause changes in DNA that are highly lethal. 

UV-C: (180-290nm) one of the most energy-consuming form of the UV that is extremely lethal.

The UV induced mutations are dimer formation, thymine- thymine dimer and thymine- cytosine dimers are commonly formed as these lesions block replication as well as transcription. 

If unrepaired, it can cause serious health effects. 

Graphical illustration of the effect of UV- radiation on DNA.

Graphical illustration of the effect of UV- radiation on DNA.

The formation of pyrimidine dimerization cause distortion in the structure of DNA and prevents the formation of replication fork during replication. 

Heat:

Heat is another mutagen that causes mutation in our DNA. when we heat the DNA, over a certain degree (>95°C), the DNA becomes denatured- two single-stranded DNA generated from the dsDNA. 

Also, extreme heat also damages DNA and breaks the phosphodiester bonds too. 

Chemical mutagens: 

Chemicals are actually dangerous for the entire world. The first mutagenic effect of the nitrogen mustard was reported by charlotte Auerbach in 1942. 

(the nitrogen mustard is a poisonous gas used during the world war 1 and 2). 

Base analogs: 

The base analogs are chemicals similar to the bases of DNA- purine and pyrimidines or structurally resemble the DNA bases.

Bromouracil and aminopurine are two common base analogs incorporated into DNA- instead of normal bases, during the process of replication. 

The 5-bromouracil are artificially synthesised molecules used in the genetic research, incorporated in a DNA in place of the thymine. 

Instead of the methyl group of the thymine, the bromouracil contains Br group- highly resemble the thymine. 

It pairs with the adenine as like the thymine and causes the mutation. See the image below, 

The pairing of adenine and 5-bromouracil.

The pairing of adenine and 5-bromouracil.

The mechanism of 5-BU action is quite interesting. As during the replication, instead of thymine, it generates the guanine which pairs with the cytosine. 

See the image below,

The bromouracil replaces the adenine and pairs with the guanine during replication.

The bromouracil replaces the adenine and pairs with the guanine during replication.

Thus the TA base pair is replaced by the GC basepair at the end of the replication and this will happens because of the tautomeric shift of 5-BU from enol to keto form. the entire mechanism of it is shown in the figure below,

Graphical illustration of the effect of base analog- bromouracil on DNA. The conversation of AT base pair to the CG base pair.

Graphical illustration of the effect of base analog- bromouracil on DNA. The conversation of AT base pair to the CG base pair.

Aminopurines: 

Another base analog is AP or amino purine which is similar to the adenine and can pair with either T or C, although pairing with C is less frequent. 

It can also cause AT to GC or GC to AT transition during the replication. 

Alkylating agents: 

Ethylnitrosourea, mustard gas and vinyl chloride are common alkylating agents add alkyl group to the DNA and damages it. 

The agents cause base-pairing errors by increasing ionization and produces gaps in the DNA strand. 

The alkylated purine bases are removed by the phenomenon called depurination, although depurination is not mutagenic and can be repaired by DNA repair pathway. 

Common alkylating agents: 

  1. Methylhydrazine 
  2. Temozolomide
  3. Dacarbazine
  4. Busulfan
  5. Thio-TEPA
  6. Carmustine
  7. lomustine
  8. Dimethyl sulphate 
  9. Ethyl ethane sulphate

“When nitrities (food preservatives) added to smoked meat, it forms nitrosamine like mutagen that can break DNA or creates DNA cross-linking.”

Intercalating agents: 

Does anything strike in your mind? 

Our EtBr- ethidium bromide used during the agarose gel electrophoresis is one of the intercalating agents.

Other intercalating agents like proflavine, acridine orange or daunorubicin operated by the same mechanism alike the EtBr. 

The molecules intercalate between the bases of DNA and disrupt its structure. If it is incorporated during the replication, it can cause frameshift mutation. It may also block transcription.

The graphical illustration of the effect of an intercalating agent on DNA.

The graphical illustration of the effect of an intercalating agent on DNA.

The intercalating agents either cause deletion or insertion and disrupts the DNA structure. 

Metal ions:

Metal ions also dangerous to our DNA as it acts in varieties of different ways. Nickel, chromium, cobalt, cadmium, arsenic, chromium and iron are some of the common metal ions cause mutations. 

The metal ions work by producing ROS, hindering DNA repair pathway, cause DNA hypermethylation or may directly damages the DNA. 

Other chemical mutagens: 

ROS- reactive oxygen species, benzene, synthetic rubber and rubber products, sodium azide, aromatic amines, alkaloids, deaminating agents and PAH are other mutagens creates different mutations. 

The base analog and intercalating agent, 5- bromouracil and acridine, respectively.

The base analog and intercalating agent, 5- bromouracil and acridine, respectively.

Biological agents: 

Viruses, bacteria and transposon (non-coding DNA sequence) are biological mutagens. 

Virus: We all know about HIV right! A causative agent of AIDS. Viruses are common mutagens that are well known to us and causes lethal health issues. 

Viruses insert their DNA into our genome and disrupt the normal function of DNA or a gene. Once it inserts DNA, the DNA is replicated, transcribed and translated viral protein instead of our own protein.

Bacteria: Some bacteria are also dangerous to for our DNA- cause inflammation. It provokes DNA damage and DNA breakage. 

Transposons: Less known biological mutagens are transposons. The transposons are non-coding DNA sequences, jumps from one place to another place in a genome and influence the function of genes. 

Unlike the viral DNA, the transposons are our own DNA believed to be originated from the retroviruses. 

We have covered an entire series on transposons and transposable elements. Please read it here. 

Effect of mutagens:

The mutagens are genotoxic- harmful to our DNA in many ways, some directly affect the DNA some indirectly. And therefore, the exact effect of each mutagen is still unknown to us. 

At the chromosomal level, the mutagens can alter the structure or number of chromosomes. As deletion, duplication, insertion, translocation, monosomy and nondisjunction are some of the chromosomal abnormalities caused by mutagens. 

The mutagens also affect or dysregulates the molecular central dogma process- replication, transcription and translation. 

At the molecular level, the mutagens create different gene mutation results in loss of function, altered function or non-functional protein. 

It also alters the codon, deletes bases, alters bases, breaks hydrogen bonds or phosphodiester bonds or changes gene expression. 

Some mutagens dysregulate cell proliferation and cell death process and thus cause cancer, those are called carcinogens.

Biological mutagens slower down the DNA repair or DNA synthesis process. 

Some of the common types of mutagens based on their effect are enlisted here: 

Teratogens: teratogens are the class of the mutagens which causes congenital malformations. 

X-rays, valproate and toxoplasma are common physical, chemical and biological teratogens, respectively. 

Carcinogens: The carcinogens are the class of mutagens induces tumour formation and thus cause cancer. Wide varieties of agents are categorised as carcinogens. X-rays/ UV-rays, Aflatoxins and retroviruses are common physical, chemical and biological carcinogens, respectively. 

Clastogens: Clastogens are the class of mutagens responsible for chromosomal- breakage, deletion, duplication and rearrangements. UV-rays, Bleomycins and HIV virus are a common type of physical, chemical and biological clastogens, respectively. 

Other non-specific mutagens: other unclassified mutagens are responsible for DNA damage and non-functioning of the DNA repair pathway. X-rays/heat, innumerable and toxoplasma are several non-specific mutagens.

The classification of mutagens bases on their effects.

The classification of mutagens bases on their effects.

Mutagens are useful…

Now, this is something interesting, scientists are using different physical, chemical or biological mutagens for various purposes. 

For example, an EtBr is used as an intercalating dye during agarose gel electrophoresis. It emits fluorescent and the DNA bands can be visualized on a gel. 

Heat method is used during the polymerase chain reaction for denaturation of DNA. This facilitates single-stranded DNA for amplification. 

The UV-rays are utilised for decontamination or sterilization process in genetics as well as microbiology. 

The UV-light destroys all the bacteria or viruses present in a culture room or laminar hood. 

Carcinogens and teratogens are used in cancer research. 

Our transposons are used as a vehicle for transferring a gene of interest at a particular location in a genome. Thus it is used in gene therapy experiments. 

Conclusion:

Thanks to our DNA repair system, almost all abnormal DNA mutations are repaired by it.

By adopting a healthy lifestyle we can save our DNA from the harmful effect of mutagens. For example, use sun scream while coming ours in sunlight. Eat healthy food and stay away from unnecessary radiations.

Mutagens are harmful, but not always. Some mutations are also beneficial to us, however, those are rare. In fact, different phenotypes for our survival are originated due to different mutations but those are not originated from the mutagens, possibly.

Quiz: 

Which one is not a mutagen?

  1. teratogen
  2. carcinogen
  3. clastogen
  4. antigen

Answer

4. Antigen

Which one is an intercalating agent?

  1. EtBr
  2. BPB
  3. Bromouridine
  4. Aminopurine

Answer

1. EtBr. Ethidium Bromide is an intercalating agent used in agarose gel electrophoresis.

UV light is also used for____

  1. Cancer therapy
  2. Sterilization
  3. PCR
  4. Gene therapy

Answer

2. sterilization

Base analogs are______

  1. similar to phosphate
  2. similar to DNA
  3. similar to purines or pyrimidines
  4. similar to deoxy sugar

Answer

3. similar to purines and pyrimidines. both are the class nitrogenous bases of DNA.

Sources: 

T. J. Schrader. Mutagens, Encyclopedia of Food Science and Nutrition. 2003; 2:4059-67.