Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells

Cao, Luchuan; Leers-Sucheta, Susan; Azhar, Salman

doi:10.1016/j.jsbmb.2003.10.007

Cited by 175 publications

(129 citation statements)

References 53 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…26 The first and rate-limiting step in the biosynthesis of steroid hormones is the transfer of cholesterol into mitochondria, which is facilitated by StAR. Functional and respiratory mitochondria with an intact mitochondrial membrane potential (DY m ) were demonstrated to facilitate StAR function and Leydig cell steroidogenesis; treatment of Leydig cells with hydrogen peroxide acutely inhibited steroidogenesis, reduced StAR and 3b-hydroxysteroid dehydrogenase protein levels, and disrupted mitochondrial functions.…”

Section: Discussionmentioning

confidence: 99%

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Hwang¹,

Liao²,

Lin³

et al. 2011

Asian J Androl

View full text Add to dashboard Cite

Testosterone replacement therapy has benefits for aging men and those with hypogonadism. However, the effects of exogenous testosterone on Leydig cells are still unclear and need to be clarified. In this report, we demonstrate that testosterone supplementation can reduce oxidative damage in Leydig cells. The TM3 Leydig cell line was used as an in vitro cell model in this study. Cytoprotective effects were identified with 100-nmol l 21 testosterone treatment, but cytotoxic effects were found with o500-nmol l 21 testosterone supplementation. Significantly reduced reactive oxygen species (ROS) generation, lipid peroxide contents and hypoxia induction factor (HIF)-1a stabilization and activation were found with 100-nmol l 21 testosterone treatment. There was a 1.72-fold increase in ROS generation in the 500-nmol l 21 compared to the 100-nmol l 21 testosterone treatment. A 1.58-fold increase in steroidogenic acute regulatory protein (StAR) expression was found in 50-nmol l 21 testosterone-treated cells (P,0.01). Chemically induced hypoxia was attenuated by testosterone supplementation. Leydig cells treated with low-dose testosterone supplementation showed cytoprotection by decreasing ROS and lipid peroxides, increasing StAR expression and relieving hypoxia stress as demonstrated by HIF-1a stabilization. Increased oxidative damage was found with o500-nmol l 21 testosterone manipulation. The mechanism governing the differential dose effects of testosterone on Leydig cells needs further investigation in order to shed light on testosterone replacement therapy. INTRODUCTIONTestosterone plays an important role in normal growth and development of male sex organs. It is also known to be a key player in glucose homeostasis and lipid metabolism. 1 More recently, gonadotrophinreleasing hormones I and II were demonstrated to stimulate testosterone production in murine Leydig cells. 2 In the testes, Leydig cells synthesize and secrete testosterone in response to luteinizing hormone, which is counter-regulated by feedback influences of testosterone and its metabolites. Testosterone levels notably decline with aging; 3,4 however, a recent report showed no correlation between androgen receptor (AR) polymorphism and the serum concentrations of total and free testosterone in elderly men. 5 The mechanism by which aged Leydig cells lose their steroidogenic function remains unclear. It was proposed that decreases in testosterone levels with aging may reflect reactive oxygen species (ROS) elevation and further disruption of the ability of Leydig cells to produce testosterone. 6,7 Mitochondrial respiration, which typically consumes about 90% of the oxygen utilized by cells, is considered to be the major source of cellular ROS. 8 ROS cause tissue damage by a variety of mechanisms including DNA damage, lipid peroxidation, protein oxidation and carbonylation, depletion of cellular thiols and activation of proinflammatory cytokine release. Mitochondrial-derived ROS were implicated in a number of disease and disorders, including neurodegenerat...

show abstract

Section: Discussionmentioning

confidence: 99%

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Hwang¹,

Liao²,

Lin³

et al. 2011

Asian J Androl

View full text Add to dashboard Cite

show abstract

“…the activation of membrane proteins like receptors, ion channels, participants of signal transduction pathways, transport proteins and membrane associated enzymes [362][363][364][365][366]), and virtually every event associated with cholesterol processing and steroidogenesis is dependent on the integrity of cell membranes [1][2][3][4][5][6]25,26,53,81,90,[367][368][369], the likelihood of steroidogenesis being adversely affected is quite high. As a result, steroidogenic cells, like other mammalian cells, are well equipped with antioxidant systems to combat free radicals [370][371][372][373][374][375]. These antioxidant systems are comprised of 1) low molecular weight agents such as vitamin E (atocopherol), vitamin C (ascorbic acid), reduced glutathione (GSH), carotenoids, flavonoids, uric acid, bilirubin, and lipoic acid; 2) iron and copper sequestering proteins such as transferrin, lactoferrin, hemopexin, albumin, and ceruloplasmin; 3) antioxidant enzymes such as superoxide dismutase (Cu,Zn-SOD, Mn-SOD), glutathione peroxidases (e.g., cytosolic glutathione peroxidase [cGPX], phospholipid hydroperoxidase glutathione peroxidase [PHGPX], plasma glutathione peroxidase [pGPX]), catalase, heme oxygenase, and thioredoxin reductase (TR); and 4) accessory antioxidant proteins such as thioredoxins, glutaredoxins, and peroxyredoxins [331,[350][351][352][353][376][377][378][379][380]…”

Section: Aging and Excessive Oxidative Stressmentioning

confidence: 99%

“…Despite this, aging leads to many oxidative changes both in the adrenocortical and the testicular Leydig cells [372,374]. These are linked, with time, to a dramatic reduction in the normally protective antioxidant defense system, thus, leading to excessive oxidative stress, and, we believe, ultimately to the decline of steroid production in the aging animals, i.e., the increase in lipid peroxidation in steroidogenic tissues may be the underlying cause of the age-related decrease in corticosterone/testosterone synthesis.…”

Section: Aging and Excessive Oxidative Stressmentioning

confidence: 99%

“…These are linked, with time, to a dramatic reduction in the normally protective antioxidant defense system, thus, leading to excessive oxidative stress, and, we believe, ultimately to the decline of steroid production in the aging animals, i.e., the increase in lipid peroxidation in steroidogenic tissues may be the underlying cause of the age-related decrease in corticosterone/testosterone synthesis. It is unclear why steroidogenic cells do not respond to this oxidant balance by simply modulating the expression of antioxidant enzymes [372,374], oxidant-sensitive transcription factors, AP-1 and NF-B [353,358,[382][383][384][385] and other stress inducible cytoprotective genes invoking cellular protective mechanisms [386]. We speculate that up-regulation does not occur in the aging animals because the continuous oxidant burden likely overwhelms the cells, leading to the failure of cellular transcriptional/translational machinery and, thus, the function of various proteins involved in the transport of cholesterol to the mitochondrial sites of P450scc.…”

Section: Aging and Excessive Oxidative Stressmentioning

confidence: 99%

“…Thus, it appears that aging in the rat adrenal [372] and testicular Leydig cells [374] is linked to a reduction in both enzymatic and non-enzymatic components of a cellular natural defense system against oxidative damage, as well as loss in the expression of major AP-1 transcription factor. Under normal stress conditions the expression of major AP-1 constituent proteins [382,402] is up-regulated, but in the aging adrenal, the only transcription factor whose expression is increased (rather than decreased) is Jun B [387], a putative repressor of AP-1 function [406][407][408][409][410].…”

Section: Aging and P38 Subfamily Of Map Kinasesmentioning

confidence: 99%

See 2 more Smart Citations

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Zaidi¹

2013

TOLSJ

View full text Add to dashboard Cite

Steroid hormones are lipophilic, low-molecular weight organic compounds all of which are derived from cholesterol. They are primarily synthesized by steroidogenic glands such as gonads (ovary and testis), the adrenal gland and, during pregnancy, by the placental trophoblasts. Limited steroid synthesis also takes place in the brain. Steroid hormones are crucial for the proper functioning of the body. They mediate a wide variety of vital physiological functions, ranging from maintaining normal reproductive function and secondary sexual characteristics, to regulating virtually every metabolic process in the body. Like many age-related endocrine disorders, aging also progressively impacts the tissue-specific synthesis and secretion of steroid hormones. The goal of this review is to summarize the effects of aging on steroid hormone synthesis and secretion by the adrenal gland and gonads of both human and experimental animal models, to describe the potential involvement of excessive oxidative stress in mediating age-related alterations in steroidogenesis, and to discuss the possible underlying mechanisms involved.

show abstract

Protective effect of gallic acid on apoptosis of sperm and in vitro fertilization in adult male mice treated with cyclophosphamide

Mehraban

Novin

Golmohammadi

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Background Alteration of free radicals (reactive oxygen species) causes mammals' sperm damage. Gallic acid (GA) is known as an antioxidant which is effective against oxidative stress. The purpose of this study was to evaluate the antioxidant effects of GA on the sperm apoptosis and in vitro fertilization (IVF) in adult male mice treated with cyclophosphamide (CP). Materials and Methods Following a pilot study to find the dose responses of GA, 40 adult male naval medical research institute (NMRI) mice (32 ± 3 g) were divided into five groups (n = 8): control, sham (normal saline, NS: 0.2 mL per day), CP (15 mg kg–1 per week; intraperitoneal, IP), GA (12.5 mg kg –1 per day; IP), and GA+CP. After the treatment, sperm parameters were analyzed. The apoptosis of sperm was measured by Annexin‐PI staining method followed by flow cytometry detection. Fertility was assessed by IVF method among the groups. Results The difference in sperm parameter and fertility rate between the control (% 80.05 ± 6.53) and cyclophosphomide groups (% 51.82 ± 10.78) was significant (P < .001) but GA plus CP (% 78.16 ± 5.71) restored the fertilization rate (P < .001). Also, a remarkable increase was noted regarding apoptotic sperm in CP group vs the control group. The comparison in the five groups shows that GA cotreatment was significantly effective in reducing the apoptosis rate caused by cyclophosphamide (P < .05). Conclusion It was ultimately attained that GA has a potent antioxidant effect which could inhibit the detrimental effect of CP on the apoptosis and fertility rate of sperm in the mouse.

show abstract

Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells

Cited by 175 publications

References 53 publications

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Protective effect of gallic acid on apoptosis of sperm and in vitro fertilization in adult male mice treated with cyclophosphamide

Contact Info

Product

Resources

About