The goal of the proposed research is to determine whether age- related reductions in sperm production in male mammals are due to intrinsic aging processes ongoing in the spermatogenic cells themselves, or rather represents the manifestation of extrinsic defects that accumulate in the supporting somatic elements. A correlary to this question is whether the germ cells, which must by definition, retain their totipotency in order to give rise to succeeding generations,are subject to the normal aging processes that affect somatic cell types. Because spermatogenesis is heavily dependent on somatic cell functions, including endocrine functions mediated by the hypothalamus-pituitary-Leydig cell axis, as well as direct interactions with supporting Sertoli cells, it may well be that age-related diminution of reproductive capacity in the male is completely the result of accumulating defects in supporting somatic functions. If this is true, it would have major significance for the potential treatment of age-related reproductive incapacity in human males. This application proposes to address these questions by analyzing specific gene expression in the germ cells as a function of age and/perturbation of supporting somatic cell functions as follows:
Specific Aim #1 - Isolate clones of genes transcribed in male embryonic germ cells but not in male embryonic somatic cells, and analyze the subsequent expression to these sequences in male germ cells at later stages in the fetus and adult.
Specific Aim #2 - Measure levels of specific mRNAs in spermatogenic cells from young, middle-aged and old animals, to see if there are any apparent age- related changes in the transcription of specific genes in these cells. Also test for an age-related reappearance of mRNAs from genes normally transcribed only in earlier stages in the germ line.
Specific Aim #3 - Compare the effects on gene expression in adult spermatogenic cells in young versus old animals of treating with: 1) EDS to eliminate testos-terone-producing Leydig cells; 2) testosterone-estrogen implants to specifically reduce testosterone levels; and 3) gamma irradiation to destroy specific spermatogenic cells.
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