Mutations caused by Environmental Factors- 3 Types

Key Concepts

• Mutation
• Mutagens
• Types of mutagens
• Physical mutagens
• Chemical mutagens
• Biological mutagens

Introduction: Mutations caused by environmental factors

Every day millions of cells transfer DNA information to proteins. However, sometimes there is a change in the DNA sequence. Any change in the DNA sequence is called a mutation. Mutations can be caused by errors in replication, transcription, or cell division. External environmental factors  can also cause changes to a cell’s DNA. 

Explanation

Some mutations seem to just happen. They are mistakes in base pairing during DNA replication. These mutations are said to be spontaneous. Many mutations are caused by environmental factors.  

Mutations caused by environmental factors are generally induced mutations. Any outside agent that causes a change in DNA is called a mutagen. Mutagenic substances include radiation, chemicals, and high temperatures. Some mutagens cause DNA to break apart. This can change the sequence of the bases. A base may disappear, or two bases may fuse together. Other mutagens cause one base to be substituted for another. 

If the mutation occurs in the non-functional part of DNA, then these mutations may remain as silent mutations. In contrast, mutations in the DNA sequence that occur in the actively transcribed region could lead to cell death and are known as lethal mutations. 

The biological effects of these mutations in the DNA are determined by the location where the DNA alters, phase of the cell cycle in which mutation occur, length or size of mutation, and any preceding mutation. 

Mutagens are classified as: 

1. Physical mutagens 
2. Chemical mutagens  
3. Biological mutagens. 

Physical mutagens: 

Physical mutagens include heat and different types of radiation. These are high energy radiations, including X- rays, gamma rays, UV rays, alpha rays, etc. These radiations can be either ionizing or non-ionizing. Radiations were the first agents that were reported to be mutagenic. Radiations are of two types ionizing and non-ionizing radiations. Most of these radiations are lethal or sub-lethal and affect cells by directly damaging the DNA or the nucleotides by cross-linking DNA, breaking chromosomes, chromosomal loss, molecular deletion of bases/DNA strand breakages. 

UV rays are non-ionizing radiations because as they have less energy as compared to X-rays. Most commonly, they are used for the process of sterilization and decontamination. They exhibit their mutagenic effect by causing base deletion, breakage of chromosomal strands, cross-linking and also forming nucleotide dimers. 

They are subdivided into UV A, UV B, and UV C rays. UV-A has a wavelength of 320nm and is known to cause dimerization of pyrimidines. This type of pyrimidine dimerization alters the DNA structure, which changes the replication fork during replication. Such dimerization may lead to several health issues. 

The wavelength of UV-B ranges from 290-320nm, and it is highly lethal to DNA. UV-C has a wavelength between 180-290nm and is the most lethal as well as carcinogenic. The ozone layer majorly absorbs these radiations. 

Ionizing radiations are high energy radiations and include X-rays and gamma rays. They primarily affect dividing cells and affect DNA as well as lipids and proteins. These radiations produce reactive ions (charged molecules or ions), which react with biological molecules.  

X-rays can induce a break in the phosphodiester bonds, which result in breakage of DNA strands when used at the dose of 350-500 rems and hence is considered lethal.  

Heat is also a type of physical mutagen. Our DNA is sensitive to temperatures above 95°C. Above this temperature, the phosphodiester bonds in DNA break resulting in the breakage of the DNA strand. 

Chemical mutagens: 

The action of chemical mutagens was first discovered in 1942. There are hundreds of chemicals that are known to be mutagenic.  

Chemical mutagens are classified into four general categories based on how they interact with the DNA. 

1. Base analogs 
2. Base altering chemicals 
3. Intercalating agents 
4. Metal ions 

• Base analogs: 

These chemical mutagens structurally resemble purines and pyrimidines and may be incorporated into DNA during DNA replication in place of the normal bases. 5-Bromouracil and aminopurine are the most common base analogs. Due to similarities in their structures with DNA bases, base analogs get inserted into the DNA structure at the time of replication.  

Aminopurine is similar to the base adenine and can form a base pair with Cytosine or Thymine (though base pairing with C is rare). 

5-Bromouracil exhibits tautomerism. All the tautomeric forms combine with different base pairs. Keto form of 5-BU mostly behaves like thymine and pairs with adenine. Whereas the enol form of 5-BU forms a complementary base pair with guanine. Thus, depending on the tautomeric form, 5-BU changes base pair from A-T to G-C or from a G-C to an A-T.  

Since these mutagens change a single base in the DNA sequence, base analogs are believed to cause point mutations. 

• Base altering chemicals: 

Base altering chemicals include hydroxylating, alkylating and deaminating agents. 

Hydroxylating agents like hydroxylamine add an OH-group to Cytosine.  

Alkylating agents induce ethyl or methyl groups in DNA resulting in DNA damage. The induction of the alkyl groups increases ionization; as a result, base-pairing errors are caused, and eventually, gaps are formed in the DNA strand. Some of the common alkylating agents are ethylnitrosourea, mustard gas, vinyl chloride, methylhydrazine, dimethyl sulfate and thio-TEPA. During the process of DNA repair, alkylating agents can be removed from the DNA by the process of depurination. It is a non-mutagenic process. 

Deaminating agent include nitrous acid, it acts on both replicating and non-replicating DNA. It causes oxidative deamination of cytosine to uracil, cytosine to thymine, and adenine to hypoxanthine. 

• Intercalating agents: 

Intercalating agents are flat, hydrophobic heterocyclic ring molecules and resemble the ring structure of base pairs. 

Since they resemble DNA base pairs, these molecules tend to insert themselves in the DNA helix, which eventually interferes with the replication, translation, and transcription process resulting in a mutation. This is known as ‘intercalating.’  

Intercalating molecules cause the DNA to stretch, and when such DNA replicates, there is an addition or deletion of one or a few base pairs opposite to the intercalated molecule. This results in frameshift mutations. 

Some examples of intercalating agents are ethidium bromide, proflavine, acridine orange, actinomycin D, or daunorubicin, etc. 

• Metal ions: 

Nickel, cobalt, chromium, cadmium, arsenic, chromium and iron are all mineral ions that generate reactive oxygen species. These metal ions cause DNA hypermethylation which leads to DNA damage and hinders the DNA repair process. 

Biological mutagens: 

• Virus 

Viruses are common biological mutagens and are well known to create several lethal health issues. The insertion of the viral genome disrupts the normal function of our DNA or genes. Once the virus is inserted in DNA, the DNA replicates, transcribes and translates viral protein instead of our own protein. This leads to the alteration of DNA. Examples include HIV, a causative agent of AIDS. Certain viruses, like the Rous sarcoma virus, has been reported to induce cancer. 

• Bacteria:  

Some bacteria induce inflammation by producing reactive oxygen species. It provokes DNA damage and DNA breakage, which causes mutation. Example: Helicobacter pylori. 

• Transposons:  

Transposons are lesser-known biological mutagens. These transposons are non-coding DNA sequences, also known as jumping genes, as they move throughout the DNA. Their addition into chromosomal DNA interrupts gene functionality. Unlike the viral DNA, the transposons are believed to be originated from the retroviruses and are a part of our own DNA. 

Summary

• Mutations lead to changes in the DNA sequence. These changes generally happen as a result of errors that occurs during DNA during replication.
• Mutations lead to genetic variation.
• However, some mutations are caused by external environmental factors and the factors that cause them are called ‘mutagens’.
• These mutations can be spontaneous or induced.
• Mutagens are physical or environmental agents that induce a genetic mutation and may increase the frequency of mutations.
• Mutagens are classified into three categories, i.e., physical mutagens, chemical mutagens and biological mutagens.
• Physical mutagens include radiations and heat. Radiations can be ionizing or nonionizing. UV rays are non-ionizing radiations and can cause damage to the DNA by forming pyrimidine dimers.
• Ionizing radiations produce reactive ions and include X-rays, alpha rays, gamma rays etc. These radiations cause cross-linking of DNA or protein, breaking of chromosomes or DNA strands, damage/deletion of bases.
• Heat is also a type of physical mutagen. Above 95°C, the phosphodiester bonds in DNA break, resulting in breakage of DNA strand.
• Chemical mutagens are classified into four general categories, based on how they interact with the DNA.

1. Base analogs
2. Base altering chemicals
3. Intercalating agents
4. Metal ions

• Base analogs structurally resemble purines and pyrimidines and may be incorporated into DNA during DNA replication in place of the normal bases. 5-Bromouracil and aminopurine are the most common base analogs. They can cause point mutations in DNA.
• Base altering mutagens include hydroxylating (add OH group), alkylating (add alkyl groups) and deaminating (add nitrous acid) agents that cause DNA damage.
• Intercalating agents are heterocyclic ring molecules and resemble the ring structure of base pairs. They insert themselves in DNA sequence during replication and cause frameshift mutations. Ethidium bromide, proflavine, acridine orange are examples of intercalating agents.
• Metal ions cause DNA hypermethylation which leads to DNA damage and hindering the DNA repair process.
• Biological mutagens include viruses, some bacteria and transposons. Viruses disruptnormal gene functions by inserting the viral genome.
• Some bacteria induce inflammation by producing reactive oxygen species.
• Transposons are jumping genes that interrupt gene functions when they are inserted in the DNA.