Genetic toxicology is the study of the effects of chemical and physical agents on genetic material. It includes the study of DNA damage in living cells that leads to cancer, but it also examines changes in DNA that can be inherited from one generation to the next. Genetic toxicology, although not called that at the time, got its start in 1927 when American geneticist Hermann J. Muller (1890-1967) demonstrated that X-rays increased the rate of gene mutations and chromosome changes in fruit flies.

The relevance of genetic toxicology is clearly evident from inheritable diseases such as phenylketonuria (an inability to metabolize phenylalanine), cystic fibrosis (lung disease), sickle cell anemia, and Tay-Sachs disease. Recent advances in molecular biology and genomic sciences are leading to a far greater understanding of the genetic cause of disease and even pointing the way to treatments.

DNA Mutations

To understand cancer it is necessary to explore the cellular changes that turn a normal cell into a malignant cell that repeatedly and uncontrollably divides. This transformation occurs when there is genetic damage or an alteration in the structure of a cell's DNA.

DNA, short for deoxyribonucleic acid, is the coding machinery of life. The beauty of DNA is its simplicity. The double helix of DNA is made of the compounds adenine (A), guanine (G), thymine (T), and cytosine (C). These chemicals are bound in long stretches as AT and CG pairs, and wrapped in sugar molecules that hold them together. Long stretches of these AT and CG combinations form genes which when "read" produce the proteins that drive our cells.

Ideally the DNA sequence would not change except in the recombining that occurs during reproduction. However, DNA damage occurs regularly as part of the cell process, and from interaction with both normal cellular chemicals and with toxic chemicals. A very robust repair mechanism rapidly and very accurately repairs the DNA damage, but if for some reason the DNA is repaired incorrectly, a mutation occurs. The mutation is a subtle or not-so-subtle change in the A, G, C, or T that make up the DNA.

Many of the mutations have no effect, some have minor effects, and a small number have life-threatening effects. If a mutation occurs in the wrong place, a cell can start to divide uncontrollably, becoming a malignant cell and causing a cancer. If a mutation occurs in our germ line cells, the mutation can be passed on to our offspring.

Mutagens

Chemicals that induce mutations in the DNA are called mutagens, and when these changes lead to cancer the chemical is called a carcinogen. Not all mutagens are carcinogens, and not all carcinogens are mutagens. In 1946 it was shown that nitrogen mustards (derived from mustard gas first used by the military in 1917 during WWI) could induce mutations in the fruit fly and reduce tumor growth in mice. Genetic toxicology developed ways to test chemical and physical agents for their mutagenic properties, and in the 1970s, Bruce Ames and others developed a cellular-based test for genetic mutations. This test became known as the Ames assay. Sophisticated variations of these tests are now required by many government regulatory agencies to test chemicals for mutagenicity before they are of approved for use.

Often it is a metabolite (breakdown product) of the compound that causes cancer, not the original compound. Ideally, a foreign chemical is made less toxic when metabolized, but sometimes a chemical can be made more toxic. This more-toxic chemical can then interact with cellular DNA or proteins and produce malignant cells. This process is called bioactivation. It is also possible for a chemical to encourage bioactivation or to accelerate the development of a cancer. Many variations of the Ames test that include liver cells were developed to simulate the metabolism of the chemical in the liver and determine if bioactivation would result in mutations.

Efforts to understand the underlying biology of cancer are ongoing. The genomic sciences are helping to explain why some people are more susceptible to cancer than others. We also know that there are many causes of cancer and that we can reduce the likelihood of developing cancer.

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