Biologic Markers in Reproductive Toxicology (1989) / Chapter Skim
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8. Assessing Transmitted Mutations in Mice
8. Assessing Transmitted Mutations in Mice
Pages 107-118
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From page 107... ...
For the purpose of this report, only end points of mutational damage to mammalian germ cells will be considered. When a chemical to which humans are exposed causes mutations in a laboratory mammal, such as the mouse, the genetic risk associated with human exposure to the chemical becomes a matter of serious concern.
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From page 108... ...
Regardless of the specifics accepted for genetic risk assessment, data on transmissible genetic effects in laboratory mammals will be indispensable-not only as a measure of end points, but also to form a standard for evaluating the usefulness of results of NMG tests as indicators of genetic risk to humans. Assessment of the genetic risk associated with exposure to a chemical includes several components: · Defensible evidence that the chemical in question has the potential to induce genetic damage to human germ cells.
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From page 109... ...
They can be classified into the following categories: cytotoxicity, cytogenetic effects, cellular biochemical responses, molecular binding, and cellular morphologic responses. Cytotoxicity Cytotoxicity to some germ cells implies that the test chemical reached the gonads and supports the assumption that the surviving cells were also exposed.
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From page 110... ...
The distinction between the two types of toxic response is difficult to make. TESTS IN MICE TO DETERMINE TRANSMITTED GENETIC EFFECTS Chemical mutagens react with various cellular and chromosomal components in different ways, so they produce different types of genetic damage.
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From page 111... ...
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From page 112... ...
Recessive Lethal Test Induced mutations in this class are lethal in the homozygous or hemizygous state, that is, when both copies of the gene are mutant alleles or when the single copy of the sex-linked gene in males is in the mutant form. Most of these lethal mutations are small deficiencies and small intragenic changes.
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From page 113... ...
This in vitro procedure allows distinction between Reimplantation loss due to dominant lethal mutations and reduced implantation due to reduced fertilization. Heritable-Translocation Test Reciprocal exchange of genetic material between nonhomologous chromosomes is much more readily inducible in male than in female germ cells.
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From page 114... ...
Cytologic evidence of nondisjunction induced in germ cells has been reported, but there is no clear evidence of a transmitted induced aneuploidy. Trisomy of AL4LE REPRODUCTIVE TOXICOLOGY the sex chromosomes appears to be the most promising biologic marker in experimental aneuploidy, because these offspring are viable.
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From page 115... ...
Male and female germ cells and the various germ cell stages differ in many ways, including ability to repair DNA lesions, length of cell-cycle time, and interval between S phases. In somatic cell systems, each cell is autonomous with respect to the fixation of aberrations.
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From page 116... ...
One clue to the molecular nature of genetic damage might come from reciprocal translocations. The question has been raised whether some human genetic disorders that have been assumed to result from single gene mutations could instead be associated with chromosomal rearrangements.
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From page 117... ...
The biologic markers that need to be examined are the individual enzymes, so that the regulation and normal function of BH4 can be understood and means of alleviating the defects in such mutants can be devised. Nondisjunction Aneuploidy resulting from chromosomal missegregation constitutes an important fraction of transmitted human genetic anomalies.
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From page 118... ...
They must be able to examine 10~° base pairs; detect MALE REPRODUCTIVE TOXICOLOGY a well-defined and wide spectrum of mutational end points; have extremely low error rates; use easily accessible samples; conserve time, people, and resources; cope with the complexity of the human genome; and recognize recombination, polymorphism, physically variable genes, somatic mutations masquerading as heritable mutations, and false paternity. Those properties also constitute one of the main reasons why appropriate mutagenesis studies in laboratory mice are necessary.
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