JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Qianqian Wang,Yaqian Yang,Pengfei Li,Ruoyun Dong,Chenhao Sun,Guanling Song,Yan Wang
Titanium dioxide nanoparticles (TiO 2 NPs) can cause apoptosis in TM4 cells; however, the underlying mechanism has not been entirely elucidated. The purpose of this study was to investigate the effects of TiO 2 NPs on ROS, Ca 2+ level, p38/AKT/mTOR pathway, and apoptosis in TM4 cells and to evaluate the role of Ca 2+ in p38/AKT/mTOR pathway and apoptosis. After exposure to different concentrations (0, 50, 100, 150, and 200 μg/mL) of TiO 2 NPs for 24 h, cell viability, ROS, Ca 2+ level, Ca 2+ -ATPase activity, p38/AKT/mTOR pathway-related proteins, apoptosis rate, and apoptosis-related proteins (Bax, Bcl-2, Caspase 3, Caspase 9, and p53) were detected. The ROS scavenger NAC was used to determine the effect of ROS on Ca 2+ level. The Ca 2+ chelator BAPTA-AM was used to evaluate the role of Ca 2+ in p38/AKT/mTOR pathway and apoptosis. TiO 2 NPs significantly inhibited cell viability, increased ROS level, and elevated Ca 2+ level while suppressing Ca 2+ -ATPase activity. TiO 2 NPs regulated the p38/AKT/mTOR pathway via increasing p-p38 level and decreasing p-AKT and p-mTOR levels. TiO 2 NPs significantly enhanced the apoptosis. NAC attenuated Ca 2+ overload and reduction in Ca 2+ -ATPase activity caused by TiO 2 NPs. BAPTA-AM alleviated TiO 2 NPs-induced abnormal expression of p38/AKT/mTOR pathway-related proteins. BAPTA-AM assuaged the apoptosis caused by TiO 2 NPs. Altogether, this study revealed that TiO 2 NPs elevated intracellular Ca 2+ level through ROS accumulation. Subsequently, the heightened intracellular Ca 2+ level was observed to exert regulation over the p38/AKT/mTOR pathway, ultimately culminating in apoptosis. These results provides a complementary understanding to the mechanism of TiO 2 NPs-induced apoptosis in TM4 cells.
研究领域:
纳米技术
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细胞生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Hong Yang,Liyang Ding,Bo Xu,Zhen Zhang,Wenjie Dai,Tiantian He,Ling Liu,Xing Du,Xufeng Fu
Di-(2-ethylhexyl)phthalate (DEHP) is a common plasticizer that has been shown to significantly negatively affect male reproductive health. On the other hand, Lycium barbarum polysaccharide (LBP) has been shown to improve reproductive function. Therefore, we hypothesized that LBP may ameliorate DEHP-induced male reproductive damage. Herein, we found that LBP could alleviate DEHP-induced testicular damage and sperm abnormalities. Furthermore, histomorphological analysis of mice testis revealed that LBP primarily ameliorated the DEHP-induced male reproductive damage by targeting Sertoli cells. Moreover, the detection of the function-related genes of Sertoli cells confirmed this finding. The serum of mice in the Control, DEHP, and DEHP+LBP groups was analyzed using non-targeted metabolomics to further elucidate the mechanism of action of LBP in improving DEHP-induced male reproductive damage. According to the results, the differential metabolites were mainly enriched in the glutamate metabolism pathway, implying that LBP may alleviate the ferroptosis-related DEHP-induced testicular injury. Related ferroptosis markers were also found in mice testis. These findings collectively suggest that LBP may ameliorate DEHP-induced testicular injury via alleviating ferroptosis in Sertoli cells. To clarify the specific mechanism, we constructed a cell model in vitro by treating TM4 cells (the Sertoli cell line) with LBP and MEHP (the in vivo DEHP metabolite). Our findings revealed that LBP can improve the function of DEHP-affected Sertoli cells. Furthermore, the analysis of lipid peroxidation, Fe 2+ content, and ferroptosis-related protein expressions demonstrated that LBP could ameliorate MEHP-induced ferroptosis in TM4 cells. To clarify the specific mechanism, glutamate metabolism-related proteins involved in the ferroptosis pathway were detected. According to the results, there were significant changes in the expression of NRF2, SLC7A11 and GPX4 proteins, which are involved in the ferroptosis glutamate metabolism pathway. Furthermore, supplementation of NRF2, SLC7A11, and GPX4 inhibitors (ML385, Erastin, and RSL3, respectively) blocked the therapeutic effect of LBP in alleviating MEHP-induced ferroptosis in TM4 cells, implying that LBP could also ameliorate MEHP-induced ferroptosis via the NRF2/SLC7A11/GPX4 pathway. In summary, these findings show that LBP can alleviate DEHP/MEHP-induced ferroptosis through the NRF2/SLC7A11/GPX4 pathway, ameliorating Sertoli cell dysfunction and improving the DEHP-induced male reproductive damage. Therefore, the clinical administration of LBP could be an effective strategy for preventing DEHP-induced male reproductive injury.
研究领域:
生殖生物学
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毒理学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2018
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IF 5.158
Shijie Li,Zhuoyue Song,Tingting Liu,Jian Liang,Jun Yuan,Zhanchi Xu,Zhanghua Sun,Xiaoping Lai,Qingping Xiong,Danyan Zhang
The purpose of this study was to investigate the effects of Ostrea rivularis polysaccharide (ORP) against testicular oxidative stress injury via kelch-like ECH-associated protein 1-nuclear erythroid 2-related factor 2/antioxidant response element (Keap1-Nrf2/ARE) pathway. In pharmacological experiments in vivo , ORP administration could dose-dependently inhibit body and testicular weight loss, ameliorate epididymal sperm quality and protect reproductive impairment in cyclophosphamide-induced male Balb/c mice. Moreover, the mechanism in vivo might be elucidated that ORP could increase expression level of Nrf2 and its downstream ARE gene battery in the testis, promote production of corresponding antioxidative enzymes and protein, and enhance Keap1-Nrf2/ARE signaling pathway to avoid male reproductive dysfunction. In addition, ORP treatment could improve survival capacity of H 2 O 2 -induced TM4 cells and its antioxidant mechanism in vitro also had been verified to activate Keap1-Nrf2/ARE signaling pathway. Overall, these results showed that ORP as a potent antioxidant could reduce reproductive oxidative stress damage related to Keap1-Nrf2/ARE pathway.
研究领域:
药理学
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生殖生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Hongmei Chang,Siqi Zhao,Yuzhu Lei,Yunhua Hu,Yizhong Yan,Guanling Song
Titanium dioxide nanoparticles (nano-TiO 2 ) can cause a reduction in sperm counts, and lactate production in Sertoli cells plays a key role in spermatogenesis. The aim of this study was to evaluate the effect of nano-TiO 2 on lactate production in mouse Sertoli cell line (TM4 cells) and to investigate whether the effect is mediated through the PI3K/AKT/HIF-1α pathway. After TM4 cells were treated with different concentrations of nano-TiO 2 for 48 h, cell viability, contents of glucose and lactate, and the expression levels of GLUT3 and key enzymes (HK1, HK2, PFKM, ENO1, LDH) during lactate production were detected. PI3K/AKT/HIF-1α pathway proteins were measured. In addition, PI3K agonist (IGF-1) was added to explore whether nano-TiO 2 regulates HIF-1α through PI3K/AKT pathway, thereby affecting the production of lactate in TM4 cells. The results showed that nano-TiO 2 significantly inhibited TM4 cell viability, increased glucose content, decreased lactate content, and downregulated the expression levels of GLUT3 and key enzymes during lactate production. Meanwhile, nano-TiO 2 decreased the expression of PI3K/AKT pathway phosphorylated proteins and HIF-1α, and IGF attenuated this effect of nano-TiO 2 . Collectively, nano-TiO 2 downregulated the expression level of proteins and enzymes related to lactate production in TM4 cells by inhibiting PI3K/AKT/HIF-1α pathway, resulting in the decrease of lactate production in TM4 cells.
研究领域:
生殖生物学
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细胞生物学
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纳米技术
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Chenjiao Miao,Zijia Wang,Xin Wang,Wanyue Huang,Xiang Gao,Zheng Cao
Deoxynivalenol (DON) is widely present in cereals and processed grains. It can disrupt the blood-testicular barrier (BTB), leading to sterility in males; however, the mechanism is unknown. In this study, 30 Kunming mice and TM4 cells were exposed to 0 or 4.8 mg/kg (28 d) and 0–2.4 μM (24 h) of DON, respectively. Histopathological findings showed that DON increased BTB permeability in mice, leading to tight junction (TJ) structural damage. Immunofluorescence results indicated that DON disrupted the localization of zonula occludens (ZO)-1. The results of protein and mRNA expression showed that the expression of ZO-1, occludin, and claudin-11 was reduced, and that the p38/GSK-3β/snail and p38/ATF-2/MLCK signaling pathways were activated in mouse testes and TM4 cells. Pretreatment with the p38 inhibitor SB203580 maintained TJ integrity in TM4 cells after exposure to DON. Thus, DON induced BTB dysfunction in mice by disrupting p38 pathway-mediated TJ expression and distribution.
研究领域:
毒理学
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生殖生物学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Jinhui Dong,Xiaohui Tong,Jing Xu,Min Pan,Lei Wang,Fei Xu,Yajuan Wang,Li Li,Tongsheng Wang
Researches have proposed that obesity might contribute to development of oligoasthenospermia. This study was performed to confirm whether obesity contributes to oligoasthenospermia as well as the underlying mechanisms in mice fed with a high fat diet (HFD). Meanwhile, the actions of metformin, a drug of well-known weight-lowering effect, on sperm quality in obese mice were investigated. Our results showed that HFD feeding reduced sperm quality and steroid hormone levels in mice, associated with disruptions in testicular histomorphology and spermatogenesis. Moreover, obesity increased sperm apoptosis. These effects could be prevented by metformin treatment in HFD-fed mice. Mechanistically, an increasement in lipid contents associated with decreased hormone-sensitive lipase (HSL) protein expression in testes in HFD-fed mice was observed, which could be improved by metformin treatment. Then, the model of TM4 mouse Sertoli cells stimulated with palmitic acid (PA) was used to investigate the potential effect of lipid retention on testicular apoptosis and sperm quality reduction. In consistent, PA exposure elevated lipid contents as well as apoptosis in TM4 cells, which could also be improved by metformin treatment. Of note, the protein expression of HSL was reduced stimulated by PA in TM4 cells, also rescued by metformin. Then, anti-apoptosis effect of metformin would be lost with the deficiency of HSL . In summary, our study propose that obesity contributes to oligoasthenospermia by increasing sperm apoptosis induced by impaired lipid hydrolysis due to HSL down-regulation, which could be prevented with metformin treatment via regulating the expression of HSL in testis in mice.
研究领域:
生殖生物学
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内分泌学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
·
2025
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IF 4.3
Qingyan Wang,Yunjie Su,Qian Yang,Trust Beta,Fei Shen,Qin Liu
Bisphenol A (BPA) is a typical endocrine disrupting chemical widely distributed in the environment and in food systems. The adverse effects of BPA on reproductive health have posed major concerns worldwide. The aim of this study was to determine the potential of epigallocatechin gallate (EGCG) to protect against BPA-induced male reproductive toxicity and investigate the underlying protective mechanism. The protective effects of EGCG on BPA-induced reproductive toxicity were investigated using male zebrafish model. The results showed that EGCG alleviated BPA-induced developmental toxicity of F1 generation of zebrafish, reversed testis disorder and combated the blood-testis barrier (BTB) damage caused by BPA in zebrafish. In order to unravel the underlying mechanism, TM4 cell - constructed BTB model was used for further study. The results indicated that EGCG counteracted the damage induced by BPA on the integrity of BTB model and reduced the autophagy caused by BPA. Furthermore, EGCG effectively inhibited the BPA-induced upregulation of the expression level of AMPK (p-AMPKα/AMPKα), significantly restored the BPA-mediated downregulation of the expression levels o。f p-mTOR/mTOR, p-AKT/AKT and Raptor. The results suggested that EGCG mitigated the BPA-induced male reproductive toxicity through maintaining the integrity of BTB by inhibiting the autophagy mediated by AMPK/AKT/mTOR signaling pathway. This study provided a strategy for combating the BPA-induced reproductive toxicity using a well-known bioactive component as a potential therapeutic approach.
研究领域:
毒理学
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生殖生物学
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环境健康
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Jinzhao Zhou,Yanwei Zhang,Ling Zeng,Xiaofei Wang,Wenpei Xiang,Ping Su
Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11–7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.
研究领域:
毒理学
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细胞生物学
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生殖健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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