Retinaldehyde Dehydrogenases as Male Contraceptive Targets

$310,505U54FY2013HDNIH

University Of Washington, Seattle WA

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Abstract

PROJECT SUMMARY (See instructions): In mammals, retinoic acid (RA) is absolutely essential for the progression of undifferentiated A spermatogonia into differentiating Al spermatogonia (the A to Al transition). The action of RA and the appearance of differentiating spermatogonia represents the commitment of the germ cell to enter meiosis. The rate-limiting step in RA synthesis is the oxidation of retinaldehyde to RA by retinaldehyde dehydrogenases (RALDHs). In the previous grant period, we demonstrated that the bisdichloroacetyldiamines (BDADs) function as male contraceptives via inhibiting the RALDHs [4, 5]. Treatment of male mice with one particular BDAD, WIN 18,446, effectively mimics testicular vitamin A deficiency and blocks spermatogonial differentiation and the production of STRAS, the classic marker of RA activity in the testis. This block is rescued by RA but not by ROL proving that the biologically important action is the inhibition of RALDHs. The cellular sources of RA and the localization of the biologically important RALDHs in the adult testis are unknown. Our hypothesis is that RALDH enzymes are a critical component in the control of RA levels in the testis and therefore, may represent excellent targets for male contraceptive agents. This proposal will investigate the expression and function of RALDHs present in the different cell types in the testis during germ cell development in mice and humans. Specfic aim 1 will investigate the expression and activity ofthe RALDHs in both the murine and human testis as well as define the transcrtipome response of the human testis to RA. Specfic Aim 2 will utilize a novel method, developed during the last grant period, for synchronizing spermatogenesis to assess retinoid levels and RALDH activites across the cycle of the seminiferous epithelium as well as the transcriptome in response to RA at the A to Al transisiton. Specfic aim 3 will elucidate which RALDH enzymes are essential for spermatogenesis via mouse knockout models. Collectively, these data will significantly enhance our understanding of how vitamin A metabolism is regulated in the testis and determine whether perturbing RALDH activity is a viable approach to male contraception.

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