PRINCIPLES OF TOXICOLOGY - Biology East Borneo

250 MUTAGENESIS AND GENETIC TOXICOLOGYformed, which may result in an alteration of some measurable cellular function. The phenotypicchanges that can be monitored by this type of test include auxotrophic changes (i.e., acquireddependence on a formerly endogenously synthesized substance), altered proteins, color differences,and lethality. It is extremely difficult to detect those alterations in mammalian DNA caused by insertionsor deletions of one or a few bases, except in rare instances where the specific protein product is knownand its formation can be monitored. It is somewhat easier in bacterial or prokaryotic systems, and thishas led to the use of bacterial or in vitro screening assays to detect potential mutagens. These issuesare discussed in greater detail in Brusick (1980, 1994).Chromosomal aberrations, the third type of genetic change, may be present as chromatid gaps orbreaks, symmetrical exchange (exchange of corresponding segments between arms of a chromosome),or asymmetric interchange between chromosomes. Point mutations can result in altered products ofgene expression, but chromosomal aberration or alteration in chromosome numbers passed on throughgerm cells can have disastrous consequences, including embryonic death, teratogenesis, retardeddevelopment, behavioral disorders, and infertility. Some naturally occurring abnormalities of humanchromosomal structure or number are shown in Table 12.2. The frequency of these events may beincreased by mutagenic agents. Because these genetic lesions may be visualized by microscopy, theyare referred to as macrolesions. One type of macrolesion is caused by an incomplete separation ofreplicated chromosomes during cell division. This is characterized by the abnormal chromosomenumbers that result in the daughter cells and may be recognized as a change in the number of haploidchromosome sets (ploidy changes) or in the gain or loss of single chromosomes (aneuploidy). A secondtype of macrolesion caused by damage to chromosome structure (clastogenic effects) is categorizedby the abnormal chromosome morphology that results.Two theories are currently available to explain the mechanism of chromosome aberration. One isthe classic “breakage-first” hypothesis. This theory assumes that the initial lesion is a break in thechromosomal backbone that is indicative of a broken DNA strand. Several possibilities exist followingsuch an event: (1) the ends may repair normally and rejoin to form a normal chromosome; (2) the endsTABLE 12.2 Examples of Human Genetic DisordersChromosome AbnormalitiesCri-du-chat syndrome (partial deletion of chromosome 5)Down’s syndrome (triplication of chromosome 21)Klinefelter’s syndrome (XXY sex chromosome constitution; 47 chromosomes)Turner’s syndrome (X0 sex chromosome constitution; 45 chromosomes)Dominant MutationsChondrodystrophyHepatic porphyriaHuntington’s choreaRetinoblastomaRecessive MutationsAl binismCystic fibrosisDiabetes mellitusFanconi’s syndromeHemophiliaXeroderma pigmentosumComplex Inherited TraitsAnencephal yClub footSpina bifidaOther congenital defects