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A Microplate Assay to Assess Chemical Effects on RBL-2H3 Mast Cell Degranulation: Effects of Triclosan without Use of an Organic Solvent
Published on: November 1, 2013
The downregulation of PEPCK mediated cuproptosis is involved in triclosan induced reproductive damage in mouse testes
Yanjun Ding1, Yifan Hong1, Xiazhu Zhou1
1Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China.
Abstract:
Triclosan (TCS) is a widely used broad-spectrum antimicrobial agent that has been demonstrated to induce damage to the male reproductive system. However, the specific mechanisms of testicular injury induced by TCS are not fully understood. In the present study, mice were treated with 0, 20 mg/kg and 40 mg/kg per day TCS from PND 56 to PND 84. Decreased sperm counts, increased sperm deformity rates, downregulation of Phosphoenolpyruvate carboxykinase (PEPCK) and cuproptosis activation were observed. In vitro, TM4 cells were exposed to 0, 5 nM and 10 nM TCS for 24 h, which induced oxidative stress damage, inhibition of PEPCK and cuproptosis activation. Furthermore, inhibition of PEPCK and cuproptosis activation was rescued by reactive oxygen species (ROS) scavengers N-Acetylcysteine (NAC). Besides, cuproptosis activation induced by TCS were rescued after overexpression of PEPCK. Drug prediction with Connectivity Map (cMap) identified flubendazole and cucurbitacin-i as potential therapeutic drug. In conclusion, this study demonstrated that TCS triggered cuproptosis activation in TM4 cells mediated by ROS storm induced PEPCK inhibition. This research also shed new insight into precise treatment of TCS-related testicular injury.
Insights
Triclosan (TCS) exposure damages male reproductive health by inhibiting PEPCK and activating cuproptosis, driven by oxidative stress. N-Acetylcysteine (NAC) and PEPCK overexpression offer potential therapeutic avenues.
Area of Science:
- Reproductive Toxicology
- Cellular Toxicology
- Antimicrobial Agent Research
Background:
- Triclosan (TCS) is a common antimicrobial with known male reproductive toxicity.
- The precise mechanisms underlying TCS-induced testicular injury remain unclear.
Purpose of the Study:
- To elucidate the mechanisms of testicular damage caused by Triclosan (TCS).
- To investigate the role of Phosphoenolpyruvate carboxykinase (PEPCK) and cuproptosis in TCS toxicity.
- To identify potential therapeutic interventions for TCS-related reproductive injury.
Main Methods:
- Mice were administered varying doses of TCS (0, 20, 40 mg/kg) from postnatal day 56 to 84.
- In vitro studies exposed TM4 cells to TCS (0, 5, 10 nM) for 24 hours.
- Reactive oxygen species (ROS) scavengers (N-Acetylcysteine) and PEPCK overexpression were used to assess rescue effects.
- Drug prediction was performed using Connectivity Map (cMap).
Main Results:
- TCS exposure led to decreased sperm counts and increased sperm deformity in mice.
- TCS induced oxidative stress, PEPCK inhibition, and cuproptosis activation in TM4 cells.
- N-Acetylcysteine (NAC) and PEPCK overexpression rescued TCS-induced inhibition and cuproptosis.
- Flubendazole and cucurbitacin-i were identified as potential therapeutic agents.
Conclusions:
- TCS triggers cuproptosis in TM4 cells via ROS-induced PEPCK inhibition.
- This study provides insights into the precise treatment of TCS-related male reproductive injury.
- Targeting PEPCK and mitigating ROS may be key therapeutic strategies.
