PRINCIPLES OF TOXICOLOGY

244 MUTAGENESIS AND GENETIC TOXICOLOGY
which results in a gene product that is partially or completely unable to perform its normal function.
Such changes may be correlated with carcinogenesis, fetal death, fetal malformation, or biochemical
dysfunction, depending on the cell type that has been affected. However, cause and effect relationships
for such correlations typically are lacking.
Initiation and termination of DNA transcription are controlled by a separate set of regulatory genes.
Most regulatory genes respond to chemical cues, so that only those genes that are needed at a given
time are expressed or available. The remaining genes are in an inactive state. The processes of gene
activation and inactivation are believed to be critical to cellular differentiation, and interruption of these
processes may result in the expression of abnormal conditions such as tumors. This represents an
example of a case in which a non-genetic event may result in tumorigenesis. Oncogenes represent an
example of a situation where activation of a genetic phenomenon may act to initiate carcinogenicity.
In contrast, loss of “tumor suppressor” genes may, by omission, result in initiation of the carcinogenic
process.
Chromosome Structure and Function
The DNA of mammalian species, including humans, is packaged in combination with specialized
proteins (predominantly histones) into units termed chromosomes, which are found in the nucleus of
the cell. The proteins are thought to “cover” certain segments of the DNA and may act as inhibitors
of expression for some regions. Each normal human cell (except germ cells) contains 46 chromosomes
(23 pairs). Chromosomes may be present singly (haploid), as in germ cells (sperm or ovum), or in
pairs (diploid), as in somatic cells or in fertilized ova. In haploid cells, all functional genes present in
the cell can be expressed. In diploid cells, one allele may be dominant over the other, and in this case,
only the dominant gene of each functional pair is expressed. The unexpressed allele is termed recessive,
and recessive genes are expressed only when both copies of the recessive type are present. Some cell
types in mammals are found in forms other than diploid. Functionally normal liver cells, for example,
are occasionally found to be tetraploid (two chromosome pairs instead of one pair).
Some features and terminology that are important to cytogenetics, or the study of chromosomes,
include:
• Karyotype—the array of chromosomes, typically taken at the point in the cell cycle known
as metaphase, which is unique to a species and forms the basis for cellular taxonomy; may
be used to detect physical or chemical damage
• Centromere—the primary constriction, which represents the site of attachment of the spindle
fiber during cell division; useful in identifying specific chromosomes, as its location is
relatively consistent
• Nucleolar organizing region—the secondary constriction, which represents the site of
synthesis of RNA, subsequently used in ribosomes for protein synthesis
• Satellite—the segment terminal to the nucleolar organizing region; useful in specific
chromosome identification
• Heterochromatin—tight-coiling region; relatively inactive
• Euchromatin—loose-coiling region; primary transcription site
Mitosis, Meiosis, and Fertilization
The process by which a somatic cell divides into two diploid daughter cells is called mitosis. The first
stage of mitosis is called prophase, during which the spindle is formed and the chromatin material
(DNA and protein) of the nucleus becomes shortened into well-defined chromosomes. During
metaphase, the centriole pairs are pulled tightly by the attached microtubules to the very center of the
cell, lining up in the equatorial plane of the mitotic spindle. With still further growth of the spindle,
the chromatids in each pair of chromosomes are broken apart, a stage called anaphase. All 46 pairs