The long-term objective of this proposal is to systematically examine, by integrating physiological, cellular and molecular approaches, the direct effects of endocrine disruptors (ED) on pubertal testicular development using a non-human primate model. Current thinking is that EDs may account for the development of male reproductive disorders in boys and a significant decline in sperm count in men reported to have occurred during the past few decades. To date, these important issues have been experimentally evaluated using rodent models, which may not serve as a most appropriate paradigm for human reproduction. The present proposal will address, for the first time, this issue using a non-human primate model. The principal investigator will determine whether treatment with Octylphenol in juvenile monkeys would exert direct effects on the testis leading to a) decrease in the number of Sertoli cells, b) decrease in testosterone production by Leydig cells, c) decrease in the number of stem (A-dark and A-pale) cells, and d) alterations in the expression and function of genes involved in endocrine/paracrine interactions in the pituitary testicular axis. A prepubertal primate """"""""testicular clamp"""""""" preparation will be used as an experimental model, and precocious testicular puberty will be induced by stimulating the testes of immature monkey in a physiological manner with invariant intermittent infusion of exogenous recombinant monkey gonadotropins (FSH and LH) and Octylphenol (2 ng/g body weight) will be administered daily. The monkeys will be castrated and the impact of Octylphenol on Sertoli cell, Leydig cell, and stem cell numbers will be determined and on the expression of genes involved in endocrine/paracrine interaction in the testis. The results from this study will identify potential sites of testicular effects of Octylphenol during puberty. Moreover, this study will also establish the prepubertal primate testicular clamp preparation as a superior model for the general examination of the effects of EDs in man.
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