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.
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.
|Haenisch, Michael; Treuting, Piper M; Brabb, Thea et al. (2017) Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. Obes Res Clin Pract :|
|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|
|Thirumalai, Arthi; Rubinow, Katya B; Cooper, Lori A et al. (2017) Dose-response effects of sex hormone concentrations on body composition and adipokines in medically castrated healthy men administered graded doses of testosterone gel. Clin Endocrinol (Oxf) 87:59-67|
|Jing, Jing; Nelson, Cara; Paik, Jisun et al. (2017) Physiologically Based Pharmacokinetic Model of All-trans-Retinoic Acid with Application to Cancer Populations and Drug Interactions. J Pharmacol Exp Ther 361:246-258|
|Arnold, Samuel L; Stevison, Faith; Isoherranen, Nina (2016) Impact of Sample Matrix on Accuracy of Peptide Quantification: Assessment of Calibrator and Internal Standard Selection and Method Validation. Anal Chem 88:746-53|
|Roth, Mara Y; Amory, John K (2016) Beyond the Condom: Frontiers in Male Contraception. Semin Reprod Med 34:183-90|
|Kocarnik, Beverly M; Boyko, Edward J; Matsumoto, Alvin M et al. (2016) Baseline estradiol concentration in community-dwelling Japanese American men is not associated with intra-abdominal fat accumulation over 10 years. Obes Res Clin Pract 10:624-632|
|Chao, Jing; Rubinow, Katya B; Kratz, Mario et al. (2016) Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men. J Clin Endocrinol Metab 101:3724-3731|
|Griswold, Michael D (2016) Spermatogenesis: The Commitment to Meiosis. Physiol Rev 96:1-17|
|Roth, M Y; Page, S T; Bremner, W J (2016) Male hormonal contraception: looking back and moving forward. Andrology 4:4-12|
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