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.

Public Health Relevance

The ideal male contraceptive agent would allow reversible control of sperm formation or function with no permanent changes to the testis or no side effects elsewhere in the body. The proteins responsibe for vitamin A metabolism have been proposed as potential male contraceptive targets. This proposal will investigate the expression and function of one group of vitamin A metabolizing proteinsi the RALDHs, and aid in determining whether their inhibition is a viable approach to male contraception.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1)
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University of Washington
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Berkseth, Kathryn E; Rubinow, Katya B; Melhorn, Susan J et al. (2018) Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men. Obesity (Silver Spring) 26:1898-1904
Rubinow, Katya B; Houston, Barbara; Wang, Shari et al. (2018) Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice. Asian J Androl 20:276-283
Chen, Yan; Zhu, Jin-Yi; Hong, Kwon Ho et al. (2018) Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol 13:582-590
Paik, Jisun; Treuting, Piper M; Haenisch, Michael et al. (2018) Can inhibition of retinoic acid biosynthesis function as a non-hormonal female contraceptive? Contraception :
Sharma, Manju; Braun, Robert E (2018) Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis. Development 145:
Rubinow, Katya B; Vaisar, Tomas; Chao, Jing H et al. (2018) Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J Clin Lipidol 12:1072-1082
Haenisch, Michael; Treuting, Piper M; Brabb, Thea et al. (2018) Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. Obes Res Clin Pract 12:93-101
Swerdloff, Ronald S; Dudley, Robert E; Page, Stephanie T et al. (2017) Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocr Rev 38:220-254
Ayoub, R; Page, S T; Swerdloff, R S et al. (2017) Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology 5:278-285
Rubinow, Katya B; Chao, Jing H; Hagman, Derek et al. (2017) Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men. Am J Physiol Endocrinol Metab 313:E528-E539

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