Chromosomal aberrations and bone marrow toxicity.

Abstract

The importance of chromosomal aberrations as a proximate cause of bone marrow toxicity is discussed. Since chemicals that can cause nondisjunction are rare, numerical aberrations (aneuploidy, polyploidy) are not ordinarily important. Many structural aberrations, however, can lead directly to cell death and so are proximate causes of toxicity when they occur. The micronucleus test which utilizes the polychromatic erythrocyte is capable of detecting agents (clastogens) that can cause such structural aberrations. Many carcinogens can be detected by this test, and recent changes in the protocol may increase the success rate. Nevertheless only a small proportion of chemicals are clastogens. The importance of cell division in the expression of chromosomal damage and the stage of the cell cycle at the time of exposure on the amount of damage is emphasized.A speculative mechanism for the relationship between chromosomal aberrations and carcinogenicity is proposed.There are two broad classes of chromosomal aberrations: numerical aberrations in which whole chromosomes are either lost or added, (e.g. trisomy-21 or Down's syndrome) and structural aberrations in which pieces of chromosome are lost, added, or translocated, for example the Philadelphia chromosome which leads to chronic myeloid leukemia.Obviously either class of aberration, if inherited, can have a significant influence on human health. These aberrations arise in fundamentally different ways. Aneuploidy, i.e., numerical aberrations involving other than a full complement of chromosomes, arise as a result of nondisjunction which is a failure of the proper distribution of chromosomes to daughter cells. Agents that interact directly with the cell's spindle mechanism are able to cause nondisjunction; there are also scattered reports which suggest that other agents may also be able to cause nondisjunction, perhaps by some indirect mechanism. Similarly, inhibition of the cell's spindle formation can lead to polyploidy, i.e., the gain or loss of whole haploid sets of chromosomes. In most tissues polyploid and aneuploid cells are rare Structural aberrations, in contrast, can lead directly to cell death and are often major contributors to toxicity. With respect to toxicity, the kinds of chromosomal aberrations (which from this point on in this paper means structural abnormalities except where otherwise indicated) may be classified in two ways: those that lead to the loss of genetic information at cell division and those that do not. This is shown diagrammatically in Figure 1. Those aberrations (of which only one of many possible types is shown) that involve a rearrangement of gene order rather than a direct loss of a gene are not cell lethal events and, hence, are not contributors to cellular toxicity. In contrast, those aberrations that lead directly to the loss of a section of genetic information are usually cell lethal events and do contribute directly to cellular toxicity. These aberrations may involve an acentric chromosomal fragment whose movement at anaphase is de...

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