Mutagenesis, carcinogenesis and other scary words – what do they really mean?
The functional headquarters of each cell is the nucleus. There are 46 chromosomes in the nucleus of human cells (in germ cells 23), which contain all of human inheritance or about 25 000 genes (a few additional genes are located in cell organelles called mitochondria). Thus each cell contains everything. The genetic information is written in three-letter words called codons in a long molecule of DNA. DNA coils itself into the double helix that was made famous by James Watson and Francis Crick in the early 1950s.
DNA is a relatively stable macromolecule. This long ribbon-like molecule winds around specific protein molecules, histones, like a string around a package. A chain of such bundles tied together by a long string coils further like the telephone cord to make a spiral. The final result is an orderly packed chromosome. Whenever needed, distinct parts of it can be revealed and a certain stretch of a gene can be used as a model for another molecule, mRNA. mRNA molecule transfers the orderly message for protein synthesis taking place in another cell organelle, the ribosome.
One codon specifies one amino acid. One mRNA molecule specifies one peptide molecule, although there may be different modifying steps in between. One or several peptides form one protein molecule. In fact this means that no human characteristics as such are inherited, but a certain set of protein molecules is, and their synthesis at the correct time and place determines the characteristics of a human being. It is actually very surprising that this multistage system can lead to an almost completely predictable end result such as demonstrated by the appearance of identical twins.
There is no error-free activity in the world, and this applies also to the transfer of genetic information. Many different factors such as viruses, foreign chemicals, oxygen radicals, or modifying factors such as hormones at the wrong place or at the wrong time may disturb this flow of events.
Mutagenic compounds are substances that can bind to some part of the DNA molecule due to their chemical reactivity. The organism has several repair mechanisms to cope with this kind of event. However, DNA-damage can lead to a mutation, e.g. a point mutation in which one codon is changed so that it will code for the wrong amino acid. This leads to the synthesis of an altered or even a totally defective protein. DNA damage can also lead to structural changes to the whole chromosome; these are called chromosomal mutations.
Mutations will often lead to cell death through apoptosis or regulated cellular suicide, but if this does not take place, a mutation may become permanent. If this occurs in an important gene involved in the regulation of cell division, e.g. in the so called p53 gene (“anti-cancer gene”) or in a proto-oncogen like the ras-gene (“cancer gene”), the consequence may be uncontrolled cell multiplication. The resulting cancer cell may be destroyed by the defence mechanisms of the organism, but if it continues multiplying and more mutations occur, the result will be the growth of a cancer. Both gene mutations and chromosomal mutations are known to be important in carcinogenesis.
Mutations occurring in germ cells may cause changes in some characteristic of the offspring. Since most mutations are deleterious, this can result in an inherited disease. On the other hand, a small minority of mutations may produce novel useful properties. Therefore the numbers of mutations have been deliberately increased in plant breeding.
Mutagens are substances that can evoke mutations in cells. DNA damage does not necessarily lead to mutations. The damage may be repaired or if the repair fails, the cell may trigger a “suicide pathway” or apoptosis leading to disintegration of the cell down to its building materials. Even if this does not take place, the organism may still identify the cancer cell and target it for destruction. If, nonetheless this damaged cell should survive, the error in the DNA may lead to a permanent change. Then the site of mutation will determine whether it is harmful.
In germ cells, mutagens may cause inheritable genetic change, for better or for worse. In the other cells of the organism (somatic cells), practically the only harmful consequence could be the initiation of a cancer cell. This requires that the mutation is somehow involved in cell cycle regulation. A change in an individual somatic cell in the organism does not otherwise cause any major impact.
Carcinogens or cancer causing agents
Carcinogens are often substances that are also mutagens. Those kinds of carcinogens are called genotoxic carcinogens, because they act by causing genetic damage. Different mutagens may have a specific preference for certain sites in the DNA, so called hot spots. The mould toxin, aflatoxin, causes preferential mutations in the codon 249 of the p53-gene and this is associated with its ability to cause liver cancer. If the preferences of a mutagenic substance are not for similarly crucial sites on DNA, carcinogenicity may not be as likely. Therefore mutagenicity does not correlate with carcinogenicity in a straightforward manner.
Carcinogens include also non-genotoxic carcinogens that are not mutagens. They may disturb hormonal balance (e.g. many substances increasing the secretion of the thyroid hormone stimulating hormone secreted from the pituitary gland to increase thyroid cancer), cause tissue damage or irritation (so called promoters: when cells are stimulated to multiply after incurring damage, the risk of cancer cell formation also increases), or they may inhibit the repair mechanisms and the enzymes involved (possibly arsenic acts in this manner). Thus there are many carcinogenic mechanisms other than mutations caused by chemicals, and often several interactive mechanisms are involved. Some mutations are being formed spontaneously all the time; therefore the factors that impair the efficiency of the repair mechanisms are very important.
Teratogen is the third scary word. Teratogens mean substances that cause birth defects if the embryo is exposed during critical periods, especially during the so-called organogenesis. This means the period when different organs such as arm or leg buds are being formed. A classic example is thalidomide. This drug causes limb defects, especially if taken during the second month of pregnancy. Adverse effects occurring later during pregnancy are often called foetal toxicity and not teratogenicity.
Mutagenicity, carcinogenicity and teratogenicity are scary words. Understanding what is behind them will help to direct both caution and actions in a useful direction.
Notes and references
One level up: Here a risk, there a risk, everywhere risks, risks!
Previous chapter: Are GM foods Frankenfoods?