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Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat.

ABSTRACT: Irradiation with 6 Gy produces a complete block of spermatogonial differentiation in LBNF1 rats that would be permanent without treatment. Subsequent suppression of gonadotropins and testosterone (T) restores differentiation to the spermatocyte stage; however, this process requires 6 weeks. We evaluated the role of Leydig cells (LCs) in maintenance of the block in spermatogonial differentiation after exposure to radiation by specifically eliminating functional LCs with ethane dimethane sulfonate (EDS). EDS (but not another alkylating agent), given at 10 weeks after irradiation, induced spermatogonial differentiation in 24% of seminiferous tubules 2 weeks later. However, differentiation became blocked again at 4 weeks as LCs recovered. When EDS was followed by treatment with GnRH antagonist and flutamide, sustained spermatogonial differentiation was induced in >70% of tubules within 2 weeks. When EDS was followed by GnRH antagonist plus exogenous T, which also inhibits LC recovery but restores follicle stimulating hormone (FSH) levels, the spermatogonial differentiation was again rapid but transient. These results confirm that the factors that block spermatogonial differentiation are indirectly regulated by T, and probably FSH, and that adult and possibly immature LCs contribute to the production of such inhibitory factors. We tested whether insulin-like 3 (INSL3), a LC-produced protein whose expression correlated with the block in spermatogonial differentiation, was indeed responsible for the block by injecting synthetic INSL3 into the testes and knocking down its expression in vivo with siRNA. Neither treatment had any effect on spermatogonial differentiation. The Leydig cell products that contribute to the inhibition of spermatogonial differentiation in irradiated rats remain to be elucidated.

SUBMITTER: Shetty G

PROVIDER: S-EPMC4860053 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat.

Shetty G G Zhou W W Weng C C Y CC Shao S H SH Meistrich M L ML

Andrology 20160318 3

Irradiation with 6 Gy produces a complete block of spermatogonial differentiation in LBNF1 rats that would be permanent without treatment. Subsequent suppression of gonadotropins and testosterone (T) restores differentiation to the spermatocyte stage; however, this process requires 6 weeks. We evaluated the role of Leydig cells (LCs) in maintenance of the block in spermatogonial differentiation after exposure to radiation by specifically eliminating functional LCs with ethane dimethane sulfonate ...[more]

PMID: 26991593

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Project description:Background: Propofol is a widely used anesthetic. Whether propofol inhibits androgen production by rat Leydig cells and the underlying mechanism remains unclear. The objective of the current study was to examine the effects of propofol exposure to rat primary immature Leydig cells and to define propofol-induced inhibition of steroidogenic enzymes in both rat and human testes in vitro. Methods: Immature Leydig cells were purified from 35-day-old male Sprague-Dawley rats and were exposed to propofol for 3 h. The androgen production by Leydig cells under basal, luteinizing hormone, 8bromo-cAMP, and steroid-substrate stimulated conditions and gene expression of Leydig cells after exposure to propofol were measured. Immature Leydig cells were treated with propofol for 3 h and switched to propofol-free medium for additional 3 and 9 h to test whether propofol-induced inhibition is reversible. 3H-Steroids were used to evaluate the direct action of propofol on cytochrome P450 cholesterol side chain cleavage (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1), and 17β-hydroxysteroid dehydrogenase 3 (HSD17B3) activities in rat and human testes in vitro. Results: Propofol significantly lowered luteinizing hormone and 8bromo-cAMP stimulated androgen production by Leydig cells after 3-h exposure. Further investigation showed that propofol down-regulated the expression of Cyp11a1 and Cyp17a1 and their proteins at 5 and 50 µM, although it up-regulated Lhcgr expression at 50 µM. Propofol significantly suppressed phosphorylation of ERK1/2 and induced ROS production in immature Leydig cells at 5 and 50 µM. Propofol significantly induced apoptosis of immature Leydig cells at 50 µM. Propofol specifically inhibited rat and human testis HSD3B activities in vitro. The half maximal inhibitory concentrations of propofol for rat and human HSD3B enzymes were 1.011 ± 0.065 and 3.498 ± 0.067 µM, respectively. The mode of action of propofol of inhibiting HSD3B was competitive when pregnenolone was added. At 50 µM, propofol did not directly inhibit rat and human testis CYP11A1, CYP17A1, and HSD17B3 activities in vitro. Conclusion: Propofol inhibits androgen production via both directly inhibiting HSD3B activity and down-regulating Cyp11a1 and Cyp17a1 expression in Leydig cells. Suppression of steroidogenic enzymes is presumably associated with the lower production of androgen by Leydig cells after propofol treatment. However, propofol-induced inhibition on androgen production is reversible.

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Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat.

Publications

Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat.

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