Metabolomics and exploratory mendelian randomization identify indole-3-propionic acid associated with
Jingyi Duan1, Xue Li1, Fei Li1
1Department of Pharmacy, Laboratory of Hepato-Intestinal Diseases and Metabolism, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Abstract:
Doxorubicin (DOX) exhibits severe side effects that restrict its clinical application. In the testes, DOX triggers apoptosis and excessive oxidative stress. Modulation of the metabolic microenvironment may contribute to the amelioration of testicular injury. However, the relationship between DOX and alterations in testicular metabolites remains elusive. In this study, the metabolic profiles of the testes and plasma were analyzed in mice with DOX-induced testicular injury. Mendelian randomization (MR) analysis was employed to prioritize candidate metabolites associated with the risk of male infertility in human cohorts. Furthermore, the roles of prioritized metabolites were validated in cells. A total of 76 metabolites in the testes and 48 metabolites in the plasma exhibited alterations, with 24 metabolites showing changes in both tissues. Although statistical significance was not maintained following FDR correction, the exploratory MR analysis prioritized indole-3-propionic acid (IPA) for its potential inverse association with male infertility. In TM4 cells, IPA attenuated DOX-induced reactive oxygen species accumulation and regulated the protein expression of the NRF2/HO-1 pathway. Collectively, these findings characterize the metabolic disturbances underlying DOX-induced testicular injury and highlight IPA as a candidate metabolite for further investigation.
Insights
Doxorubicin (DOX) causes testicular damage by increasing oxidative stress. Indole-3-propionic acid (IPA) shows potential in protecting against this injury and may reduce male infertility risk.
Area of Science:
- Metabolomics
- Toxicology
- Reproductive Biology
Background:
- Doxorubicin (DOX) chemotherapy causes severe testicular toxicity, limiting its use.
- Oxidative stress and apoptosis in testes are key mechanisms of DOX-induced injury.
- Metabolic microenvironment alterations may influence testicular response to DOX, but this is poorly understood.
Purpose of the Study:
- To investigate metabolic profile changes in testes and plasma following DOX administration.
- To identify key metabolites associated with DOX-induced testicular injury and male infertility risk.
- To validate the protective role of candidate metabolites in cellular models.
Main Methods:
- Metabolomic profiling of mouse testes and plasma after DOX treatment.
- Mendelian randomization (MR) analysis using human cohorts to link metabolites with male infertility.
- In vitro validation of identified metabolites in TM4 cells exposed to DOX.
Main Results:
- Significant alterations in 76 testicular and 48 plasma metabolites were observed, with 24 common changes.
- Exploratory MR analysis suggested indole-3-propionic acid (IPA) is inversely associated with male infertility risk.
- IPA mitigated DOX-induced reactive oxygen species and modulated the NRF2/HO-1 pathway in TM4 cells.
Conclusions:
- DOX-induced testicular injury is characterized by widespread metabolic disturbances.
- IPA emerges as a promising candidate metabolite for ameliorating DOX testicular toxicity.
- Further research into IPA's therapeutic potential for male infertility is warranted.
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