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KEY POINTS

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  • Genetic toxicology assesses the effects of chemical and physical agents on the hereditary material (DNA) and on the genetic processes of living cells.

  • Oncogenes are genes that stimulate the transformation of normal cells into cancer cells.

  • Genetic toxicology assays serve to identify mutagens for purposes of hazard identification, and to characterize dose–response relationships and mutagenic mechanisms.

  • A broad range of short-term assays for genetic toxicology serve to identify many mutagens and address the relationship between mutagens and cancer-causing agents.

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INTRODUCTION

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Genetic toxicology assesses the effects of chemical and physical agents on both DNA and on the genetic processes of living cells. This chapter addresses the assays for qualitative and quantitative assessment of cellular changes induced by chemical and physical agents, the underlying molecular mechanisms for these changes, and how such information can be incorporated in risk assessments.

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HEALTH IMPACT OF GENETIC ALTERATIONS

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Somatic Cells

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Mutational alteration of proto-oncogenes can lead to overexpression of their growth-stimulating activity, whereas mutations that inactivate tumor-suppressor genes, which normally restrain cellular proliferation, free cells from their inhibitory influence. The action of oncogenes is genetically dominant in that a single active oncogene is expressed even though its normal allele is present in the same cell. Among chromosomal alterations that activate proto-oncogenes, translocations are especially prevalent. A translocation can activate a proto-oncogene by moving it to a new chromosomal location with a more active promoter, where its expression is enhanced. Unlike oncogenes, the cancer-causing alleles that arise from tumor-suppressor genes are typically recessive in that they are not expressed when they are heterozygous.

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Six acquired characteristics are essential for the formation of all tumors irrespective of tumor type and species. These include (1) self-sufficiency in growth signals, (2) insensitivity to antigrowth signals, (3) evasion of apoptosis, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) tissue invasion and metastasis. It seems probable that there is no specific order for obtaining these characteristics.

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Gene mutations, chromosome aberrations (morphologic abnormality), and aneuploidy (abnormal number of chromosomes) are all implicated in the development of cancer. Many mutagens and clastogens (chromosome-breaking agents) contribute to carcinogenesis as initiators; however, mutagens, clastogens, and aneugens also may contribute to multiple genetic alterations.

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Germ Cells

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The relevance of gene mutations to health is evident from the many disorders often caused by base-pair substitutions or small deletions that are inherited as simple Mendelian characteristics. Many genetic disorders (e.g., cystic fibrosis, phenylketonuria, and Tay–Sachs disease) are caused by the expression of recessive mutations. These mutations are mainly inherited from previous generations and are expressed when an individual inherits the mutant gene from both parents.

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Besides causing diseases that exhibit Mendelian inheritance, gene mutations undoubtedly contribute to human disease through the genetic component of disorders with a complex etiology such as heart disease, hypertension, and ...

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