Dominant-Lethal Mutations and Heritable Translocations in Mice

Abstract

By acceptance of t h i s a r t i c l e , t h e publisher o r r e c i p i e n t acknowledges t h e U.S. Government's r i g h t t o r e t a i n a nonexclusive, r o y a l t y -f r e e l i c e n s e i n and t o any copyright covering tke a r t i c l e . U.S. Department of Energy under c o n t r a c t W-7405-eng-26 w i t h t h e UnionCarbide Corporation. SUMMARYThe primordial germ cells originate in the regloti of the caudal end of the primitive streak, root of the allantois, and yolk sac splanchuopleure, and migrate to the gonadal ridges where they divide to form the oogonia of the female and gonocytes of the male. In the female, the transition to oocytes occurs in utero, and the female mammal is born with a finite number of oocytes that cannot be replaced. By contrast, the gonocytes of the male initiate divisions soon after birth to form the spermatogonial stem cells, which persist throughout reproductive life of the male and are capable of regenerating the seminiferous epithelium after injury. As a result of these basic differences in gametogenesis, the response of the male and female to radiation and chemicals is different. Any loss of oocytes in the female cannot be replaced, and if severe enough, will result in a shortening of the reproductive span. In the male, a temporary sterile period may be induced owing to destruction of the differentiating spermatogonia, but the stem cells are the most resistant spermatogonial type, are capable of repopulating the seminiferous epithelium, and fertility usually returns. The response of both the male and female changes with development of the embryonic to the adult gonad, and with differentiation and maturation in the adult. The primordial germ cells, early oocytes, and differentiating spermatogonia of the adult male are unusually sensitive to the cytotoxic action of noxious agents, but each agent elicits a specific response owing to the intricate biochemical and physiological changes associated with development and maturation of the gametes. The relationship of germ cell killing to fertility is direct, and long-term fertility effects can be predicted from histological analysis of the gonads. The relationship to genetic effects on the other hand, is indirect, and acts primarily by limiting the cell stages available for testing, by affecting the distribution of mitotically active stem cells among the different stages of the mitotic cycle, and thereby, changing both the type and frequency of genetic effects observed. INTRODUCTIONThe level of our understanding of the effect of radiation, chemicals, pollutants, and noxious agents in general on the gonads, and the relationship of these effects to fertility and to transmission of genetic damage is dependent upon our understanding of the normal process of germ cell development. Some of the problems to be discussed here were phrased over a century ago, but it is only within the last thirty years that the direct lineage between primordial germ cells and the definitive gametes has been firmly established, and significant progress i...