Trends in Endocrinology & Metabolism
ReviewInhibiting vitamin A metabolism as an approach to male contraception
Section snippets
Spermatogenesis and the search for a male contraceptive
Providing men and women with the ability to choose when they want to bring a child into the world is essential in today's society. To suit the extensive range of people's needs and wants, ongoing development and refinement of contraceptive technologies for both men and women is required. The use and distribution of an oral contraceptive for women was first approved in 1960 [1]. However, the production of a similar product for men has yet to be successful. An effective male contraceptive should
The metabolism and signaling of vitamin A in the testis
In mammals, vitamin A is usually transported via serum as retinol (ROL) bound to retinoid-binding proteins, and conversion of this retinoid for either storage (retinyl esters) or use (RA) takes place in target tissues [11]. Retinol is taken up by cells via the membrane-bound receptor STRA6 and, once inside, the conversion of ROL to RA is controlled by a two-step enzymatic process [12] (Figure 2a). An understanding of which retinoid-metabolizing enzymes are expressed in the mammalian testis is
The regulation of spermatogonial differentiation by vitamin A
The changes in gene expression that drive the A to A1 transition are still being elucidated; however, it is known that RA plays an essential role in rodents [10]. When adult male mice are made VAD by maintaining them on a vitamin A-deficient diet for 2–3 months, all differentiated germ cells are lost from the seminiferous epithelium, and only type A spermatogonia and Sertoli cells remain 10, 40 (Figure 1). This indicates that removing RA blocks the ability of undifferentiated spermatogonia to
Inhibiting vitamin A function - an effective male contraceptive?
The optimal target for testicular contraception should be organ-specific or enriched, essential for germ cell production, and accessible to inhibition by small molecules. Vitamin A is essential for the development and health of many different organ systems, and it appears that there are numerous vitamin A metabolizing enzymes, some of which are enriched in specific tissue types [13]. Expression of Aldh1a2 and Aldh9a1 appears to be selectively enriched in adult testis, and a recent study
Conclusions
Women currently have numerous choices for methods of contraception whereas men only have two, condoms or vasectomy, and the latter is not an appropriate option for men who wish to conceive children in the future. There has been a great deal of work attempting to develop a hormone-based male contraceptive [9]; however, issues regarding drug delivery, efficacy and side effects of hormone administration to men have made this approach problematic. Indeed, despite over 30 years of research into male
References (49)
- et al.
The use of hormonal contraception and its protective role against endometrial and ovarian cancer
Best Pract. Res. Clin. Obstet. Gynaecol.
(2010) Undifferentiated primate spermatogonia and their endocrine control
Trends Endocrinol. Metab.
(2010)Cytology of the testis and intrinsic control mechanisms
- et al.
Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes
Drug Metab. Pharmacokinet.
(2006) - et al.
The cytosolic aldehyde dehydrogenase gene (Aldh1) is developmentally expressed in Leydig cells
FEBS Lett.
(1997) Ontogeny of Rdh9 (Crad3) expression: ablation causes changes in retinoid and steroid metabolizing enzymes, but RXR and androgen signaling seem normal
Biochim. Biophys. Acta
(2007)Functional characterization of mouse RDH11 as a retinol dehydrogenase involved in dark adaptation in vivo
J. Biol. Chem.
(2005)Multiple and additive functions of ALDH3A1 and ALDH1A1: cataract phenotype and ocular oxidative damage in Aldh3a1−/−/Aldh1a1−/− knock-out mice
J. Biol. Chem.
(2007)Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid
J. Biol. Chem.
(1999)- et al.
Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms
Pharmacol. Ther.
(2006)
The cycle of the seminiferous epithelium in humans: a need to revisit?
J. Androl.
A revised model for spermatogonial expansion in man: lessons from non-human primates
Reproduction
Spermatogonial stem cells in higher primates: are there differences from those in rodents?
Reproduction
Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes
Microsc. Res. Tech.
Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 2: changes in spermatid organelles associated with development of spermatozoa
Microsc. Res. Tech.
Advances in male contraception
Endocr. Rev.
The key role of vitamin A in spermatogenesis
J. Clin. Invest.
Regulation and perturbation of testicular functions by vitamin A
Reproduction
From carrot to clinic: an overview of the retinoic acid signaling pathway
Cell. Mol. Life Sci.
Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis
J. Androl.
Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in mice
Toxicol. Sci.
The so-called ‘testis-specific aldehyde dehydrogenase’ corresponds to type 2 retinaldehyde dehydrogenase in the mouse
Histochem. Cell Biol.
Cellular expression of retinal dehydrogenase types 1 and 2: effects of vitamin A status on testis mRNA
J. Cell. Physiol.
Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis
Endocrinology
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GC-MS metabolomics reveals dysregulated lipid metabolic pathways and metabolites in diabetic testicular toxicity: Therapeutic potentials of raffia palm (Raphia hookeri G. Mann & H. Wendl) wine
2021, Journal of EthnopharmacologyCitation Excerpt :It occurs when the hyperglycemia-generated free radicals surpass the testicular antioxidant system (Obode et al., 2015). The antioxidant activities of both metabolites have been established (Mueller and Boehm, 2011; Sirmali et al., 2014) as well as their therapeutic role in male reproductive dysfunction (Azari et al., 2014; Goralczyk et al., 1992; Hogarth et al., 2011; Vernet et al., 2006). The presence of vitamin A aldehyde correlates with the activation of retinal metabolism in DSG-LD group (Table 2) which plays a key role in spermatogenesis by regulating germ cell differentiation (Hogarth and Griswold, 2010).
Changes in retinoid metabolism and signaling associated with metabolic remodeling during fasting and in type I diabetes
2021, Journal of Biological ChemistryAnalysis of vitamin A and retinoids in biological matrices
2020, Methods in EnzymologyCitation Excerpt :atRA and its metabolite 4-oxo-atRA, are potent transcriptional activators of nuclear retinoic acid receptors (RARs) (Larange & Cheroutre, 2016; Topletz et al., 2015). atRA is believed to be responsible for the biological activity of vitamin A, such as regulating expression of genes important in reproduction and development (Clagett-Dame & Knutson, 2011; Duester, 2008; Hogarth, Amory, & Griswold, 2011), in energy homeostasis (Blaner, 2019; Chen & Chen, 2014; Zhao et al., 2012), in maintenance of epithelia (McCullough, Northrop-Clewes, & Thurnham, 1999), in regulation of cell cycle and differentiation (Liu, Ly, Hu, & Wan, 2014; Mezquita & Mezquita, 2019) and in immunity (Grizotte-Lake et al., 2018; Iwata et al., 2004; Larange & Cheroutre, 2016). The fact that the activation of RARs is driven by changes in ligand (atRA) concentrations, has resulted in a need for robust analytical methods to detect and quantify retinoids.
Crosstalk in the non-classical signal transduction of testosterone and retinol in immature rat testes
2020, SteroidsCitation Excerpt :There is evidence that the activation of intracellular RAR is responsible for retinoic acid-induced rapid effects (in less than 15 min) on spontaneous synaptic current frequency facilitation at the embryonic neuromuscular synapse [36]. Retinoids are essential for immature testicular development and male fertility [38]. Retinol interacts with the Sertoli cell plasma membrane-bound receptor and transporter, Stra6, which internalizes and converts retinol by a two-step enzymatic process to retinoic acid [39].
FGF2 Has Distinct Molecular Functions from GDNF in the Mouse Germline Niche
2018, Stem Cell ReportsCitation Excerpt :Additionally, it is well known that RA is the master regulator of the seminiferous epithelial cycle (Hogarth et al., 2013). The RA concentration in testes is determined by the balance between RA production and metabolism (Hogarth et al., 2011). Furthermore, the length of the seminiferous epithelial cycle varies depending on the animal species and is determined by the germ cell genotype (França et al., 1998; Sugimoto et al., 2012).
Role of retinoic acid receptor (RAR) signaling in post-natal male germ cell differentiation
2015, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :Altogether these data support the idea that Rara/Rxrb heterodimers, in which Rara is activated by atRA and Rxrb is transcriptionally silent, are instrumental to normal spermiation. Investigating how atRA-activated RAR/RXR heterodimers act to drive spermatid release has potentially important implications for the development of new male contraception protocols [59]. Spermiation is highly sensitive to androgen receptor (AR) activity [60], cell adhesion and integrity of the Sertoli cell cytoskeleton [61–63].