Aging and Luteinizing Hormone Effects on Reactive Oxygen Species Production and DNA Damage in Rat Leydig Cells1

Beattie, Matthew C.; Chen, Haolin; Fan, Jinjiang; Papadopoulos, Vassilios; Miller, Paul J.; Zirkin, Barry R.

doi:10.1095/biolreprod.112.107052

Cited by 51 publications

(47 citation statements)

References 46 publications

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“…In addition to reduced expression and activity of proteins required for the conversion of cholesterol to testosterone, damage to steroidogenic machinery as a result of perturbation in the balance between the generation of reactive oxygen species (ROS), and their neutralization by antioxidants, is hypothesized to underlie the decreased testosterone production by aged LCs (21, 23, 24, 94, 96). In other rodent models of premature aging, including the senescence accelerated SAMP8 mouse line (97–99) and premature aging induced by d -galactose administration (100, 101), primary testicular dysfunction is associated with increased testicular ROS production.…”

Section: Discussionmentioning

confidence: 99%

A young testicular microenvironment protects Leydig cells against age‐related dysfunction in a mouse model of premature aging

et al. 2018

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Testicular Leydig cells (LCs) are the primary source of circulating androgen in men. As men age, circulating androgen levels decline. However, whether reduced LC steroidogenesis results from specific effects of aging within LCs or reflects degenerative alterations to the wider supporting microenvironment is unclear; inability to separate intrinsic LC aging from that of the testicular microenvironment in vivo has made this question difficult to address. To resolve this, we generated novel mouse models of premature aging, driven by CDGSH iron sulfur domain 2 ( Cisd2) deletion, to separate the effects of cell intrinsic aging from extrinsic effects of aging on LC function. At 6 mo of age, constitutive Cisd2-deficient mice display signs of premature aging, including testicular atrophy, reduced LC and Sertoli cell (SC) number, decreased circulating testosterone, increased luteinizing hormone/testosterone ratio, and decreased expression of steroidogenic mRNAs, appropriately modeling primary testicular dysfunction observed in aging men. However, mice with Cisd2 deletion (and thus premature aging) restricted to either LCs or SCs were protected against testicular degeneration, demonstrating that age-related LCs dysfunction cannot be explained by intrinsic aging within either the LC or SC lineages alone. We conclude that age-related LC dysfunction is largely driven by aging of the supporting testicular microenvironment.-Curley, M., Milne, L., Smith, S., Jørgensen, A., Frederiksen, H., Hadoke, P., Potter, P., Smith, L. B. A Young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging.

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Section: Discussionmentioning

confidence: 99%

A young testicular microenvironment protects Leydig cells against age‐related dysfunction in a mouse model of premature aging

et al. 2018

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“…In Leydig cells since cAMP-induced phosphorylation of ERK1/2, a kinase involved in steroidogenesis, is mediated by mitochondrial ROS (50). However, abnormally high ROS levels decrease testosterone production by Leydig cells (6,51,52). This decrease is mediated, at least in part, by inhibition mitochondrial function and STAR protein levels (44) as well as repression of NUR77 activating function (53).…”

Section: Discussionmentioning

confidence: 99%

“…This decrease is mediated, at least in part, by inhibition mitochondrial function and STAR protein levels (44) as well as repression of NUR77 activating function (53). In addition, an alteration of the redox environment is also characteristic of ageing cells (52). Consequently, Leydig cells have diverse defense mechanisms in place to neutralize excessive ROS production in order to maintain an optimal level required for adequate steroidogenesis.…”

Section: Discussionmentioning

confidence: 99%

The Transcription Factor MEF2 Is a Novel Regulator of Gsta Gene Class in Mouse MA-10 Leydig Cells

et al. 2015

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Testosterone is essential for spermatogenesis and the development of male sexual characteristics. However, steroidogenesis produces a significant amount of reactive oxygen species (ROS), which can disrupt testosterone production. The myocyte enhancer factor 2 (MEF2) is an important regulator of organogenesis and cell differentiation in various tissues. In the testis, MEF2 is present in Sertoli and Leydig cells throughout fetal and adult life. MEF2-deficient MA-10 Leydig cells exhibit a significant decrease in steroidogenesis concomitant with a reduction in glutathione S-transferase (GST) activity and in the expression of the 4 Gsta members (GST) that encode ROS inactivating enzymes. Here, we report a novel role for MEF2 in ROS detoxification by directly regulating Gsta expression in Leydig cells. Endogenous Gsta1-4 mRNA levels were decreased in MEF2-deficient MA-10 Leydig cells. Conversely, overexpression of MEF2 increased endogenous Gsta1 levels. MEF2 recruitment to the proximal Gsta1 promoter and direct binding on the -506-bp MEF2 element were confirmed by chromatin immunoprecipitation and DNA precipitation assays. In MA-10 Leydig cells, MEF2 activates the Gsta1 promoter and cooperates with Ca(2+)/calmodulin-dependent kinases I to further enhance Gsta1 promoter activity. These effects were lost when the -506-bp MEF2 element was mutated or when a MEF2-Engrailed dominant negative protein was used. Similar results were obtained on the Gsta2, Gsta3, and Gsta4 promoters, suggesting a global role for MEF2 factors in the regulation of all 4 Gsta genes. Altogether, our results identify a novel role for MEF2 in the expression of genes involved in ROS detoxification, a process essential for adequate testosterone production in Leydig cells.

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“…However, changes in pituitary function are likely not responsible for the lower steroidogenic capacity of the Leydig cells suggesting that some mechanism within the testis, or the Leydig cells themselves, is primarily responsible for reduced testosterone production [Chen et al 2002;Wang et al 1999]. Recent data suggest that oxidative stress increases with age and interferes with the activity and expression of steroidogenic enzymes in the Leydig cells, leading to decreased testosterone production [Beattie et al 2013]. Estradiol is also a product of testicular steroidogenesis.…”

Section: Introductionmentioning

confidence: 99%

Alterations in the estrogen environment of the testis contribute to declining sperm production in aging rats

Clarke

Pearl

2014

Systems Biology in Reproductive Medicine

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Testicular function, specifically, production of testosterone by Leydig cells, diminishes during aging. Estradiol is also produced by the testis and potentially acts in an autocrine or paracrine manner to help regulate spermatogenesis. However, changes in estradiol concentration or receptor expression within the testis during aging remain unclear. This study was designed to test the hypothesis that the estrogen environment of the testis is altered during aging and that these changes are associated with declining sperm production. Sprague Dawley rats were examined at three, 15, 18, and 21 months of age to detail changes in sperm production and testicular concentration of testosterone and estradiol; five rats were used at three and 21 months and three rats were used at 15 and 18 months. Daily sperm production declined 49% from 15 to 21 months of age. Testicular concentrations of estradiol declined 53% from 15 to 21 months of age; testosterone concentrations were not significantly different. These results suggest that declines in intra-testicular estradiol may contribute to declining sperm production. We further tested our hypothesis by treating rats once every third day with a subcutaneous injection of estradiol valerate (1 µg/kg) from 15 to 18 months of age. Estradiol was increased 54% in treated animals while testosterone was unaffected. Estrogen receptor alpha (ESR1) expression was significantly reduced from 15 to 18 months and expression in estrogen-treated animals was significantly higher than age-matched controls. Additionally, ESR1 expression in 18 month treated animals was not different from 15 months of age. Importantly, daily sperm production in 18 month treated animals was 22% higher than age-matched controls; thus, treatment prevented approximately half of the decline observed in control animals. Collectively, our results suggest that estrogen is involved in maintaining optimum spermatogenesis in adult rats and that estrogen treatment may attenuate the age-associated loss in sperm production.

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Aging and Luteinizing Hormone Effects on Reactive Oxygen Species Production and DNA Damage in Rat Leydig Cells1

Cited by 51 publications

References 46 publications

A young testicular microenvironment protects Leydig cells against age‐related dysfunction in a mouse model of premature aging

A young testicular microenvironment protects Leydig cells against age‐related dysfunction in a mouse model of premature aging

The Transcription Factor MEF2 Is a Novel Regulator of Gsta Gene Class in Mouse MA-10 Leydig Cells

Alterations in the estrogen environment of the testis contribute to declining sperm production in aging rats

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