Involvement of inducible nitric oxide synthase in stress-impaired testicular steroidogenesis

Kostic, Tatjana S.; Andrić, Silvana A.; Marić, D.; Stojilković, Stanko S.; Kovačević, Radmila

doi:10.1677/joe.0.1630409

Cited by 34 publications

(28 citation statements)

References 33 publications

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“…The ability of stress to inhibit reproductive function is well documented (27,28,37,38,39,40,50,55,56,64,72). A sharp decline of serum testosterone is one of the first signs of IMO.…”

Section: Discussionmentioning

confidence: 99%

“…The animals were raised in controlled environmental conditions (22 Ϯ 2°C; 12:12-h light-dark cycle, lights on at 7:00 A.M.) with food and water ad libitum. IMO was performed in the morning (from 0800 to 1000) by the method of Kvetnansky (41) described previously (37,39,40,50). Briefly, IMO rats were bound in the supine position to a wooden board by fixing the rat limbs by thread to the wooden board, but head motion was not limited.…”

Section: Animals and Stress Modelmentioning

confidence: 99%

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Repeated immobilization stress disturbed steroidogenic machinery and stimulated the expression of cAMP signaling elements and adrenergic receptors in Leydig cells

Stojkov

Janjic

Bjelic

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Stojkov NJ, Janjic MM, Bjelic MM, Mihajlovic AI, Kostic TS, Andric SA. Repeated immobilization stress disturbed steroidogenic machinery and stimulated the expression of cAMP signaling elements and adrenergic receptors in Leydig cells. Am J Physiol Endocrinol Metab 302: E1239 -E1251, 2012. First published February 28, 2012 doi:10.1152/ajpendo.00554.2011.-This study was designed to evaluate the effect of acute (2 h daily) and repeated (2 h daily for 2 or 10 consecutive days) immobilization stress (IMO) on: 1) the steroidogenic machinery homeostasis; 2) cAMP signaling; and the expression of receptors for main markers of 3) adrenergic and 4) glucocorticoid signaling in Leydig cells of adult rats. The results showed that acute IMO inhibited steroidogenic machinery in Leydig cells by downregulation of Scarb1 (scavenger receptor class B), Cyp11a1 (cholesterol side-chain cleavage enzyme), Cyp17a1 (17␣-hydroxylase/17,20 lyase), and Hsd17b3 (17␤-hydroxysteroid dehydrogenase) expression. In addition to acute IMO effects, repeated IMO increased transcription of Star (steroidogenic acute regulatory protein) and Arr19 (androgen receptor corepressor 19 kDa) in Leydig cells. In the same cells, the transcription of adenylyl cyclases (Adcy7, Adcy9, Adcy10) and cAMPspecific phosphodiesterases (Pde4a, Pde4b, Pde4d, Pde7a, Pde8a) was stimulated, whereas the expression of the genes encoding protein kinase A subunits were unaffected. Ten times repeated IMO increased the levels of all adrenergic receptors and ␤-adrenergic receptor kinase (Adrbk1) in Leydig cells. The transcription analysis was supported by cAMP/testosterone production. In this signaling scenario, partial recovery of testosterone production in medium/content was detected. The physiological significance of the present results was proven by ex vivo application of epinephrine, which increased cAMP/testosterone production by Leydig cells from control rats in greater fashion than from stressed. IMO did not affect the expression of transcripts for Crhr1/Crhr2 (corticotropin releasing hormone receptors), Acthr (adrenocorticotropin releasing hormone receptor), Gr (glucocorticoid receptor), and Hsd11b1 [hydroxysteroid (11-␤) dehydrogenase 1], while all types of IMO stimulated the expression of Hsd11b2, the unidirectional oxidase with high affinity to inactivate glucocorticoids. Thus, presented data provide new molecular/transcriptional base for "fight/adaptation" of Leydig cells and new insights into the role of cAMP, epinephrine, and glucocorticoid signaling in recovery of stress-impaired Leydig cell steroidogenesis.

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“…The ability of stress to inhibit reproductive function is well documented (27,28,37,38,39,40,50,55,56,64,72). A sharp decline of serum testosterone is one of the first signs of IMO.…”

Section: Discussionmentioning

confidence: 99%

Section: Animals and Stress Modelmentioning

confidence: 99%

Repeated immobilization stress disturbed steroidogenic machinery and stimulated the expression of cAMP signaling elements and adrenergic receptors in Leydig cells

Stojkov

Janjic

Bjelic

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…In addition, acute restraint stress has also been shown to increase adult plasma corticosterone, and reduce plasma dihydrotestosterone and 3a-androstanediol, but not the aromatized metabolite estradiol in rats (Walf & Frye 2012). Other studies in adult rats and mice (Pomerantz & Pitelka 1998, Kostic et al 1999 have shown that acute and chronic immobilization stress can result in a decrease in serum androgen concentrations, mediated by increased nitric oxide (NO) signaling in the testes, which specifically inhibits P450c17 activity (Kostic et al 1999). It has been suggested that NO inhibits the activity of cytochrome P450 complexes by binding to the heme iron (Quaroni et al 1996) or to the sulfhydryl groups in these enzymes (Snyder et al 1996).…”

Section: Figurementioning

confidence: 98%

Adrenal steroidogenesis following prenatal dexamethasone exposure in the spiny mouse

Quinn¹,

Ratnayake²,

Castillo‐Melendez³

et al. 2014

Journal of Endocrinology

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Antenatal stress disturbs the development of the fetal hypothalamic-pituitary-adrenal axis and adrenal steroidogenesis. We investigated the effect of brief maternal exposure to high glucocorticoids (dexamethasone (DEX)) at mid-and late-pregnancy on adrenal structure and production of steroids in spiny mouse. Pregnant spiny mice were treated for 60 h with 125 mg/kg DEX or saline s.c. by osmotic minipump at day 20 (0.5) or 30 (0.75) of gestation. Immunohistochemical expression of steroidogenic acute regulatory-protein (StAR), 3b-hydroxysteroid dehydrogenase (3bHSD), 17-hydroxylase,17-20lyase (P450C17), and cytochromeb5 (CYTB5) was determined in adrenals on postnatal (P) day 170G20. DHEA, testosterone, and cortisol were measured by RIA. Maternal DEX at 20 days significantly reduced the expression of STAR, P450C17 (CYP17A1), and CYTB5 in the adrenal zona reticularis (ZR) of adult offspring, with greater change in male vs female offspring (P!0.05). Plasma DHEA was decreased in male offspring from DEX-treated (6.84G1.24 ng/ml) vs saline-treated (13G0.06 ng/ml; PZ0.01) dams, and the DHEA:cortisol ratio was lower in males (P!0.05). Testosterone levels increased in male offspring from DEX (266.03G50.75 pg/ml) vs saline (83.47G32.3 pg/ml, P!0.05)-treated dams. DEX treatment at 0.75 gestation had no significant effect on any parameters measured. This study shows that brief exposure to excess glucocorticoid has long-term impacts on the ZR and adrenal steroidogenesis, affecting the secretion of DHEA and testosterone in male offspring, an effect produced at 0.5 but not at 0.75 gestation. DHEA is important for brain development, and its suppression in adult life might contribute to the neurobehavioral pathologies that can arise after illness and stress during pregnancy.

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“…A short, 2-h session of IMO in rats produces a sharp decline of plasma T levels and blocks the LH-induced T production in hemitestis preparations incubated in vitro, and these actions have been attributed to endogenous NO activity (29). Further studies have led to the proposal that the involvement of NO in stress is due to activation of testicular inducible nitric oxide synthase (iNOS) (30,31). In addition, multiple lines of evidence support the conclusion that IMO is associated with increased NOS mRNA and protein levels in the brain cortex (36) and paraventricular nucleus (7) and in the HPA axis (27).…”

mentioning

confidence: 99%

Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress

Weissman¹,

Sottas²,

Zhou³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Weissman BA, Sottas CM, Zhou P, Iadecola C, Hardy MP. Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress. Am J Physiol Endocrinol Metab 292: E615-E620, 2007. First published October 10, 2006; doi:10.1152/ajpendo.00412.2006.-Immobilization stress (IMO) induces a rapid increase in glucocorticoid secretion [in rodents, corticosterone CORT)] and this is associated with decreased circulating testosterone (T) levels. Nitric oxide (NO), a reactive free radical and neurotransmitter, has been reported to be produced at higher rates in tissues such as brain during stress. The biosynthesis of T is also known to be dramatically suppressed by NO. Specifically, the inducible isoform of nitric oxide synthase (iNOS) was directly implicated in this suppression. To assess the respective roles of CORT and NO in stress-mediated inhibition of T production, adult wild-type (WT) and inducible nitric oxide synthase knockout (iNOS Ϫ/Ϫ ) male mice were evaluated. Animals of each genotype were assigned to either basal control or 3-h IMO groups. Basal plasma and testicular T levels were equivalent in both genotypes, whereas testicular weights of mutant mice were significantly higher compared with WT animals. Exposure to 3-h IMO increased plasma CORT and decreased T concentrations in mice of both genotypes. Testicular T levels were also affected by stress in WT and mutant males, being sharply reduced in both genotypes. However, the concentrations of nitrite and nitrate, the stable metabolites of NO measured in testicular extracts, did not differ between control and stressed WT and iNOS Ϫ/Ϫ mice. These results support the hypothesis that CORT, but not NO, is a plausible candidate to mediate rapid stress-induced suppression of Leydig cell steroidogenesis.

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Involvement of inducible nitric oxide synthase in stress-impaired testicular steroidogenesis

Cited by 34 publications

References 33 publications

Repeated immobilization stress disturbed steroidogenic machinery and stimulated the expression of cAMP signaling elements and adrenergic receptors in Leydig cells

Repeated immobilization stress disturbed steroidogenic machinery and stimulated the expression of cAMP signaling elements and adrenergic receptors in Leydig cells

Adrenal steroidogenesis following prenatal dexamethasone exposure in the spiny mouse

Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress

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