ROS inhibit the expression of testicular steroidogenic enzyme genes via the suppression of Nur77 transactivation

Lee, Seung-Yon; Gong, Eun-Yeung; Hong, Chang Yee; Kim, Keon-Hee; Han, Jung‐Soo; Ryu, Jae Chun; Chae, Ho Zoon; Yun, Chul‐Ho; Lee, Keesook

doi:10.1016/j.freeradbiomed.2009.09.004

Cited by 79 publications

(58 citation statements)

References 81 publications

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“…13 Although ROS are considered cytotoxic, they have also been recognized as important signalling molecules. Lee et al 48 showed that ROS signalling-mediated c-Jun upregulation suppressed the expression of steroidogenic enzyme genes by inhibiting Nur77 transactivation, resulting in the reduction of testicular steroidogenesis. These findings may provide a mechanistic explanation for the observed age-related decline in testicular steroid hormone production.…”

Section: Discussionmentioning

confidence: 99%

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Wang¹,

Wang²,

Chen³

et al. 2012

Asian J Androl

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Several studies have suggested that stress and ageing exert inhibitory effects on rat Leydig cells. In a pattern similar to the normal process of Leydig cell ageing, stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression that then results in decreased testosterone secretion. We hypothesized that chronic stress accelerates the degenerative changes associated with ageing in Leydig cells. To test this hypothesis, we established a model of chronic stress to evaluate stress-induced morphological and functional alterations in Brown Norway rat Leydig cells; additionally, intracellular lipofuscin levels, reactive oxygen species (ROS) levels and DNA damage were assessed. The results showed that chronic stress accelerated ageing-related changes: ultrastructural alterations associated with ageing, cellular lipofuscin accumulation, increased ROS levels and more extensive DNA damage were observed. Additionally, testosterone levels were decreased. This study sheds new light on the idea that chronic stress contributes to the degenerative changes associated with ageing in rat Leydig cells in vivo.

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Section: Discussionmentioning

confidence: 99%

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Wang¹,

Wang²,

Chen³

et al. 2012

Asian J Androl

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“…Furthermore, we assessed the intracellular ROS levels and found that ROS levels were elevated by wortmannin, suggesting that autophagy is required for the clearance of ROS. Because ROS are harmful to steroidogenesis in Leydig cell, [13][14][15][16] accumulation of ROS during the ageing process will result in a low level of testosterone. It may be possible that mitochondrial dysfunction in ageing cells contributes to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…12 It has been demonstrated that reactive oxygen species (ROS) inhibit StAR expression and testosterone production in Leydig cells through activating p38 mitogen-activated protein kinase or c-Jun. [13][14][15][16] Because mitochondria are the crucial sources of ROS in aerobic eukaryotic cells, androgen deficiency in aged males may be attributed to dysfunctional mitochondria owing to an accumulation of ROS. [17][18][19] Autophagy is a cellular degradative pathway that involves the delivery of cytoplasmic cargo to lysosomes, and it is essential for cell survival, differentiation, development and homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Li¹,

Chen²,

Chen³

et al. 2011

Asian J Androl

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Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males, but the mechanism remains unclear. In this study, we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity. Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production. In Leydig cells from young and aged rats, treatment with wortmannin, an autophagy inhibitor, inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production. In contrast, treatment with rapamycin, an autophagy activator, enhanced LH-stimulated steroidogenesis in Leydig cells from aged, but not young, rats. Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin. Furthermore, an increased level of ROS, induced by H 2 O 2 , resulted in LH-stimulated steroidogenic inhibition. Finally, knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells, which were associated with increased intracellular ROS level. These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells, which might be influenced by intracellular ROS levels.

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“…Several studies have shown that steroidogenesis is inhibited by ROS (Tsai et al 2003, Stocco, Wells & Clark 1993, Kodaman, Aten & Behrman 1994, Lee et al 2009, Abidi et al 2008). …”

Section: Resultsmentioning

confidence: 99%

“…Aldosterone and 7-ketocholesterol are known oxidative stress inducers whereas progesterone has antioxidant properties (Leonarduzzi et al, 2006, Gramajo et al, 2010, Lee et al, 2009, Calo et al, 2010, Queisser et al, 2011, Ozacmak et al, 2009. Moreover, progesterone and pregnenolone are androgen precursors which have been suggested to play a major role in prostate cancer cell survival (Locke et al 2008).…”

Section: Wwwintechopencommentioning

confidence: 99%