Differential Effects of Aging on Adrenocdrticotropin Receptors, Adenosine 3′5′-Monophosphate Response, and Corticosterone Secretion in Adrenocortical Cells from Sprague-Dawley Rats*

Popplewell, Philip Y.; Tsubokawa, Makoto; Ramachandran, J.; Azhar, Salman

doi:10.1210/endo-119-5-2206

Cited by 49 publications

(31 citation statements)

References 47 publications

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“…As reported earlier and further confirmed here, aging decreased the corticosterone production in isolated adrenocortical cells (Popplewell et al, 1986). Aging-induced adrenal lipid peroxidation was also significantly increased both under basal condition and following exposure to either enzymatic or non-enzymatic pro-oxidants.…”

Section: Discussionsupporting

confidence: 91%

“…Aging in both humans (Lamberts et al , 1997;Harper et al , 1999;Shifren & Schiff, 2000;Burger et al ., 2002;Arlt, 2004;Dharia & Parker, 2004;Harman, 2005;Kaufman & Vermeulen, 2005;Veldhuis et al , 2005) and experimental animals (Popplewell et al ., 1986;Belloni et al ., 1992;Liao et al ., 1993;Zirkin & Chen, 2000;Cao et al ., 2004;Wang & Stocco, 2005 and references therein) is associated with a significant decline in the synthesis and secretion of steroid hormones. Work over the past several years from this laboratory has led to the realization that inefficient mobilization of stored cholesteryl esters and transport of free cholesterol from the putative 'cholesterol pool' to mitochondrial CYP11A1 (P450scc) sites for enzymatic conversion of cholesterol to pregnenolone and other steroid hormones are the two critical events responsible for age-related loss of steroidogenic response (Popplewell & Azhar, 1987;Liao et al ., 1993).…”

Section: Introductionmentioning

confidence: 99%

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Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

et al. 2007

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SummaryThe current studies were initiated to investigate whether excessive oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogenactivated protein kinase (MAPK) signaling pathways. Western blot analysis indicated that aging caused increased phosphorylation and activation of rat adrenal p38 MAPK, but not the ERK1/2 or JNK1/2. Lipid peroxidation measurements (an index of cellular oxidative stress) indicated that adrenal membranes from young animals contained only minimal levels of endogenous thiobarbituric acid-reactive substances (TBARS), and exposure of membranes to enzymatic and non-enzymatic pro-oxidants enhanced TBARS formation approximately 12-and 20-fold, respectively. The adrenal membranes from old animals showed much more susceptibility to lipid peroxidation and exhibited roughly 4-to 6-fold higher TBARS formation than young controls both under basal conditions and in response to pro-oxidants. Qualitatively similar results were obtained when lipid peroxide formation was measured using a sensitive FOXRS (ferrous oxidation-xylenol orangereactive substances) technique. We next tested whether aging-induced excessive oxidative insult alters steroidogenesis through modulation of MAPK signaling pathway. Treatment of adrenocortical cells from old rats with specific p38 MAPK inhibitors restored Bt2cAMP-stimulated steroidogenesis ~60-70% of the value seen in cells of young animals. Likewise, pretreatment of cells with reactive oxygen species (ROS) scavengers MnTMPyP and N -acetyl cysteine also partially rescued age-induced loss of steroid production. In contrast, simultaneous treatment of cells with ROS scavengers and p38 MAPK inhibitor did not produce any additional effect suggesting that both types of inhibitors exert their stimulatory action through inhibition of p38 MAPK activation. Collectively, these results indicate that p38 MAPK functions as a signaling effector in oxidative stress-induced inhibition of steroidogenesis during aging.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

et al. 2007

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“…In rats, this steroidogenic decline is found in adrenocortical (Malamed & Carsia 1983, Popplewell et al 1986, Cheng et al 1990) and testicular Leydig cells (Bethea & Walker 1979, Tsitouras et al 1979, Liao et al 1993, Chen et al 1994 of several strains and is a progressive defect increasing in impact as the rat ages from 5 months to 12, 18, and 24 months (Malamed & Carsia 1983, Popplewell et al 1986, Liao et al 1993, Medicherla et al 2002. The major functional alteration occurs distal to sites of tropic hormone interaction and cAMP generation (Tsitouras et al 1979, Popplewell et al 1986, Liao et al 1993 and is primarily related to a defect in the transport of free cholesterol to CYP11A1 (P450 scc ) sites within the mitochondria where the conversion of cholesterol to pregnenolone (parent steroid) begins with side-chain cleavage (Popplewell & Azhar 1987, Liao et al 1993.…”

Section: Introductionmentioning

confidence: 92%

Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway

Abidi

Zhang²,

Zaidi³

et al. 2008

Journal of Endocrinology

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Previous studies from this laboratory identified excessive oxidative stress as an important mediator of age-related decline in steroid hormone production. Here, we investigated whether oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogen-activated protein kinase (MAPK) signaling pathways. To accomplish these studies, we employed a highly responsive mouse adrenocortical cell line, Y1-BS1 cells that secrete large quantities of steroids when stimulated with lipoprotein plus hormone. Treatment of these cells with superoxide, H 2 O 2 or 4-hydroxy-2-nonenal (HNE) significantly inhibited steroid production and increased phosphorylation and activation of p38 MAPK. None of the treatments altered the phosphorylation of either extracellular signal-regulated kinases or c-Jun N-terminal kinases (JNKs). Pretreatment of Y1-BS1 cells with MnTMPyP, a cell-permeable superoxide-dismutase/ catalase mimetic reactive oxygen species (ROS scavenger), completely prevented the superoxide-and H 2 O 2 -mediated inhibition of steroid production. Likewise, antioxidant N-acetylcysteine completely blocked the HNE-induced loss of steroidogenic response. Incubation of Y1-BS1 cells with either MnTMPyP or NAC also upregulated Bt 2 cAMP and Bt 2 cAMPChHDL 3 -stimulated steroid synthesis, indicating that endogenously produced ROS can inhibit steroidogenesis. Inhibition of p38 MAPK with SB203580 or SB202190 upregulated the basal steroid production and also prevented the oxidant-mediated inhibition of steroid production. mRNA measurements by qPCR indicated that Y1-BS1 adrenal cells predominantly express p38 MAPKa isoform, along with relatively low-level expression of p38 MAPKg. By contrast, little or no expression was detected for p38 MAPKb and p38 MAPKd isoforms in these cells. Transfection of Y1-BS1 cells with either caMKK3 or caMMK6 construct, the upstream p38 MAPK activators, decreased steroidogenesis, whereas transfection with dnMKK3 or dnMKK6 plasmid DNA increased steroidogenesis. Similarly, transfection of cells with a dnp38 MAPKa or dnp38 MAPKb construct also increased steroid hormone production; however, the effect was less pronounced after expression of either dnp38 MAPKg or dnp38 MAPKd construct. These results indicate that activated p38 MAPK mediates oxidant (excessive oxidative stress)-induced inhibition of adrenal steroidogenesis.

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“…Some of these variations may be due to various compensatory mechanisms operating in rodent models, increased or decreased disposal rates of the corticosterone or changes in binding proteins. But, when specifically challenged in vitro, isolated adrenocortical cells [295][296][297][298][299][300][301][302] of older male rats of several different strains show significantly less hormone response to maximal ACTH or cAMP stimulation than do cells from young or adult animals. Further studies from our own laboratory have shown that these changes in steroid hormone production and secretion are not a function of reduced ACTH receptors, cAMP production, cAMP phosphodiesterase, steroidogenic enzymes or lipoprotein-mediated cholesterol delivery and the major alteration in the respective cell types occurs distal to cAMP generation [297,298,[303][304][305].…”

Section: Experimental Animalsmentioning

confidence: 99%

“…But, when specifically challenged in vitro, isolated adrenocortical cells [295][296][297][298][299][300][301][302] of older male rats of several different strains show significantly less hormone response to maximal ACTH or cAMP stimulation than do cells from young or adult animals. Further studies from our own laboratory have shown that these changes in steroid hormone production and secretion are not a function of reduced ACTH receptors, cAMP production, cAMP phosphodiesterase, steroidogenic enzymes or lipoprotein-mediated cholesterol delivery and the major alteration in the respective cell types occurs distal to cAMP generation [297,298,[303][304][305]. In contrast, several reports from one laboratory, however, suggests that the adrenocortical cells isolated from aged female rats in fact possess an enhanced capacity to secrete corticosterone in response to ACTH stimulation than cells from young or adult animals [306][307][308][309][310].…”

Section: Experimental Animalsmentioning

confidence: 99%

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Zaidi¹

2013

TOLSJ

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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.

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Differential Effects of Aging on Adrenocdrticotropin Receptors, Adenosine 3′5′-Monophosphate Response, and Corticosterone Secretion in Adrenocortical Cells from Sprague-Dawley Rats*

Cited by 49 publications

References 47 publications

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

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