Testosterone production by a Leydig tumor cell line is suppressed by hyperthermia-induced endoplasmic reticulum stress in mice

Kim, Jung‐Hak; Park, Sun-Ji; Kim, Tae-Shin; Kim, Jin Man; Lee, Dong Seok

doi:10.1016/j.lfs.2015.12.042

Cited by 38 publications

(25 citation statements)

References 41 publications

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“…An increasing number of studies have indicated that ER stress played an important role in the biosynthesis of testosterone by aggravating apoptosis, oxidative stress, etc 20,35 In this study, the impaired steroidogenic ability of the testicular Leydig cells was accompanied by ER stress in the HC diet-induced male testosteronedeficient rats. To further explore the relationship between impaired biosynthesis of testosterone and ER stress in the testicular Leydig cells, a chemical chaperone that stabilizes protein conformation and improves ER protein-folding capacity, 4-PBA, was used.…”

Section: Discussionmentioning

confidence: 66%

“…Consequent to testicular free cholesterol deposition, HC diet-fed rats exhibited evident dilated ER in the Leydig cells, which means that ER dysfunction might be present. The up-regulated expression of sensor ATF6 was evident in the testis of HC diet-fed rats, indicating the important role of the ATF6 pathway during ER stress.From previous reports and our results, we can conclude that excess cholesterol may act as an inducer of ER stress in the testicular microenvironment.An increasing number of studies have indicated that ER stress played an important role in the biosynthesis of testosterone by aggravating apoptosis, oxidative stress, etc20,35 In this study, the impaired steroidogenic ability of the testicular Leydig cells was accompanied by ER stress in the HC diet-induced male testosteronedeficient rats. Changes in ER lipid composition under cholesterol overload may disrupt ER membrane functions and cause an accumulation of misfolded and unfolded ER proteins, which can trigger ER stress.…”

mentioning

confidence: 66%

“…25 Some studies have reported that diet and environmental factors could lead to apoptosis and regulate steroidogenesis in Leydig cells, decreasing testosterone production. 18,20,35 To further analyse the mechanism of the HC diet-induced reduction in testosterone levels, testicular histomorphological changes and 3β-HSD, which are localized only in the Leydig cells and often used as a Leydig cell marker, 36 Although cholesterol is an essential substrate for testosterone biosynthesis, excess cholesterol can be toxic. 37 Free cholesterol accumulation can increase the free cholesterol/phospholipid ratio in cellular membranes and form needle-shaped cholesterol crystals, leading to a consequent dysfunction of integral membrane proteins and cellular organelle disruption.…”

Section: Discussionmentioning

confidence: 99%

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HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells

Jiang

Zhang

et al. 2019

J Cellular Molecular Medi

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Emerging epidemiological studies indicate that hypercholesterolaemia is a risk factor for testosterone deficiency. However, the underlying mechanism is unclear. Testicular Leydig cells are the primary source of testosterone in males. To identify the effect and mechanism of cholesterol overload on Leydig cell function, rats were fed with a HC (HC) diet to induce hypercholesterolaemia. During the 16‐week feeding period, serum testosterone levels were reduced in a time‐dependent manner in rats fed the HC diet. Accordingly, these steroidogenic enzymes within the Leydig cells, including steroidogenic acute regulatory protein (StAR), cholesterol side‐chain cleavage cytochrome P450 (P450scc) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD), were down‐regulated. Notably, the HC‐fed rats showed evident endoplasmic reticulum (ER) stress in the testis, including a dilated ER as an evident pathological change in the Leydig cell ultrastructure, up‐regulated ER stress biomarker (binding immunoglobulin protein) levels and activation of the activating transcription factor 6 (ATF6)‐related unfolded protein response pathway. Further analysis showed that when 4‐phenyl butyric acid (4‐PBA) was used to block ER stress in HC‐fed rats for 8 weeks, the testosterone deficiency was significantly alleviated. Our findings suggested that high dietary cholesterol intake affected serum testosterone levels by down‐regulating steroidogenic enzymes and that activated ER stress might serve as the underlying mechanism.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells

Jiang

Zhang

et al. 2019

J Cellular Molecular Medi

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“…A reduced level of testosterone was suggested to be caused by oxidative damage to the Leydig cell population and might be related to the decreased number of Leydig cells (Midzak, Chen, Papadopoulos, & Zirkin, ). Leydig cell damage causes a decrease in testosterone levels which plays an important role in the process of spermatogenesis (Kim, Park, Kim, Kim, & Lee, ). In addition, another study showed that MLT regulates testosterone levels (Casao et al, ).…”

Section: Discussionmentioning

confidence: 99%

The effects of high‐fructose corn syrup consumption on testis physiopathology—The ameliorative role of melatonin

Aslankoç

Özmen

2019

Andrologia

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This study investigated the ameliorative role of melatonin (MLT) and the effects of a long‐term intake of high‐fructose corn syrup (HFCS) on the male reproductive system. Thirty‐six male Sprague Dawley rats were randomly divided into 3 groups as follows: Control, HFCS and HFCS + MLT. Testis and epididymal weights were measured. Malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities, total testosterone levels, testicular histopathological damage scores were evaluated, and immunohistochemical analyses were performed on testicular tissue. Epididymal weights were significantly lower in the HFCS + MLT group than those of the control and HFCS groups. MDA was significantly increased, while SOD and CAT activities were reduced in the HFCS group compared with the control group. Administration of melatonin significantly increased SOD and CAT activities in the HFCS + MLT group. Histopathological evaluation revealed slight hyperaemia and oedema in the stromal tissue of rat testes in the HFCS group. Sperm count and Johnsen's testicular biopsy score (JTBS) were significantly decreased in the HFCS group. Immunohistochemical analysis revealed that HSP, iNOS, MDA, OPN and VEGF values were significantly increased in the HFCS group. However, melatonin ameliorated the immunohistochemical scoring. Our results showed that a long‐term intake of HFCS caused testicular damage. Melatonin may be a promising pharmacological agent against testicular toxicity induced by HFCS.

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“…Jung-Hak Kim et al found endoplasmic reticulum stress suppressed testosterone production in mice Leydig tumor cell line [25]. Our prior work found endoplasmic reticulum stress response (ERS) inducing by Tg reduced progesterone production and steroidogenic enzyme expression in a goat granulosa cell line [26].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of XBP1 by RNAi in Mouse Granulosa Cells Promotes Apoptosis, Inhibits Cell Cycle, and Decreases Estradiol Synthesis

Wang

Zhao

Lin

et al. 2017

IJMS

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Granulosa cells are crucial for follicular growth, development, and follicular atresia. X-box binding protein 1 (XBP1), a basic region-leucine zipper protein, is widely involved in cell differentiation, proliferation, apoptosis, cellular stress response, and other signaling pathways. In this study, RNA interference, flow cytometry, western blot, real-time PCR, Cell Counting Kit (CCK8), and ELISA were used to investigate the effect of XBP1 on steroidogenesis, apoptosis, cell cycle, and proliferation of mouse granulosa cells. ELISA analysis showed that XBP1 depletion significantly decreased the concentrations of estradiol (E2). Additionally, the expression of estrogen synthesis enzyme Cyp19a1 was sharply downregulated. Moreover, flow cytometry showed that knockdown of XBP1 increased the apoptosis rate and arrests the cell cycle in S-phase in granulosa cells (GCs). Further study confirmed these results. The expression of CCAAT-enhancer-binding protein homologous protein (CHOP), cysteinyl aspartate specific proteases-3 (caspase-3), cleaved caspase-3, and Cyclin E was upregulated, while that of Bcl-2, Cyclin A1, and Cyclin B1 was downregulated. Simultaneously, CCK8 analysis indicated that XBP1 disruption inhibited cell proliferation. In addition, XBP1 knockdown also alters the expression of Has2 and Ptgs2, two essential genes for folliculogenesis. Collectively, these data reveal a novel critical role of XBP1 in folliculogenesis by regulating the cell cycle, apoptosis, and steroid synthesis of mouse granulosa cells.

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Testosterone production by a Leydig tumor cell line is suppressed by hyperthermia-induced endoplasmic reticulum stress in mice

Cited by 38 publications

References 41 publications

HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells

HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells

The effects of high‐fructose corn syrup consumption on testis physiopathology—The ameliorative role of melatonin

Knockdown of XBP1 by RNAi in Mouse Granulosa Cells Promotes Apoptosis, Inhibits Cell Cycle, and Decreases Estradiol Synthesis

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