ABSTRACT
Well over a century of research in teratology-the evaluation of congenital defects, their causes, and the mechanisms responsible for their genesis (derived from the Greek teras [monster] and logos [study])— has shown that developing mouse embryos are vulnerable to both structural defects and functional alterations arising from many teratogenic inuences. Regardless of the cause, these agents act by perturbing normal developmental processes during sensitive periods of development. For this reason, scientists engaged in mouse developmental pathology experiments must have a rm grasp of the processes responsible for normal development so that they may better understand the pathogenic consequences of disturbing biochemical reactions, molecular pathways, and cellular interactions. The major events of normal development have been recounted briey in Chapter 4 and the references listed therein. This chapter concisely reviews the primary etiologies and mechanisms by which developmental malformations have been induced in mice. Additional insight regarding causes and mechanisms of abnormal development, and advanced methods for investigating them, of relevance to mice may be gained from books and book chapters devoted to developmental toxicology.3,24,28,37,38,45,66
Multiple inuences have been shown to incite structural malformations in developing mice.74 These may be broadly classied as genetic mutations, pathogens, physical agents, and toxicants. Genetic mutations
Etiologic Agents That Cause Defective Development in Mice ................................................................ 99 Fundamental Principles of Teratology ................................................................................................... 100
Developmental Stage ........................................................................................................................ 100 Differential Sensitivity ...................................................................................................................... 103 Dose .................................................................................................................................................. 105 Tissue Specicity .............................................................................................................................. 106 Maternal Toxicity .............................................................................................................................. 106
Pathogenic Mechanisms of Defective Development ............................................................................. 106 Excessive Cell Death ........................................................................................................................ 106 Interference with Programmed Cell Death (Apoptosis) ................................................................... 107 Reduced Cell Proliferation ................................................................................................................ 107 Failed Cellular Interactions ............................................................................................................... 108 Inhibited Morphogenetic Movements ............................................................................................... 108 Reduced Biosynthesis of Essential Components .............................................................................. 109 Intracellular pH ..................................................................................................................................110
Conclusion ..............................................................................................................................................110 References ...............................................................................................................................................110
commonly but not always arise from altered expression of elements that control gene transcription, cell growth, or cell stability, and may act to produce either increased or decreased quantities of the protein. In such cases, the miscommunication associated with disrupted protein cascades promotes malformations by preventing or warping normal developmental processes rather than causing damage to pre-existing cells and organs. In contrast, pathogens, physical agents, and toxicants often act by damaging cells (including stem cells), thereby resulting in death or inammation within differentiating cell populations or organs. Examples of agents from each of these classes are showcased in Table 5.1. In some instances, damage to the conceptus is exacerbated by concurrent maternal illness.2
