Specific gene mutations induce male infertility in mice without observable effects on spermatogenesis or testicular steroidogenesis. The primary goal of the proposed studies is to elucidate the actions of these gene mutations on sexual behavior, sperm function, and the endocrine system. The studies combine genetics, behavioral science, endocrinology, and molecular biology in a physiological approach to the critical assessment of gene mutations named hemimelic extra toes, hightail, hypothyroid, little, pygmy, and stubby. The following parameters of the reproductive biology of each mouse will be quantified: mating behavior, sexual arousal, fertilizing capacity of sperm in vivo and in vitro, sperm viability, motility, and velocity, pattern of sperm maturation antigens as detected with monoclonal antibodies, and serum levels of LH, FSH, growth hormone, prolactin, thyroxine, and testosterone. One aspect of the proposed studies is the designing of hormone replacement experiments which may provide insight into hormonal requirements of specific reproductive processes. The ramifications of the gene mutations will be assessed by comparing mutant mice and their normal siblings. The power of the experimental approach is evidenced by the fact that the primary difference between the infertile mouse and its normal sibling is the single-gene mutation. The experimental results will be important for understanding the phenotypic effects of the gene mutations that cause male infertility. Significantly, the gene mutations have the potential of being important experimental tools for deciphering the complex network of processes required for successful male reproduction. The mutation mice may also provide superior animal models for investigations of the etiology and therapeutic treatments of idiopathic male infertility. In addition, the mutant mouse models of male infertility will be utilized in research designed to achieve a long-term career goal of the candidate: the elucidation of the molecular basis of the genetic control of steroidogenic enzymes in mouse testes. A progam is discussed that will provide the additional training necessary to permit the candidate to incorporate into his research program the methodologies of steroidogenic enzyme purification and molecular biology.
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