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Shikonin targets to m6A-modified oxidative damage pathway to alleviate benzene-induced testicular injury
Lin Han1, Wei Zhang1, Jingyu Wang1
1Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
Abstract:
Benzene exposure causes reproductive toxicity through oxidative damage. However, the specific mechanisms of benzene-induced testicular damage and the potential therapeutic drugs remain poorly understood. In the present study, C57BL/6J mice have been exposed to 0 and 150 mg/kg benzene for four weeks. Then, we found that benzene exposure induced testicular damage in mice, mainly manifested by decreased testicular coefficients, abnormal semen parameters and HE-stained intraepithelial vacuolation. On the mechanism, benzene exposure activated Kelch Like ECH Associated Protein 1/Nuclear factor-erythroid 2 related factor 2 (Keap1/Nrf2) and NF-κB signaling pathway, then promoted apoptosis and inflammatory responses in testes. In vitro, massive reactive oxygen species (ROS) production and a large number of apoptotic cells were observed after 1,4-BQ treatment of GC-2 cells. Furthermore, benzene altered the expression of three important RNA methylation modulator genes, methyltransferase-like 3 (Mettl3), AlkB homolog 5 (Alkbh5) and YTH domain containing 2 (Ythdc2). Moreover, both m6A modification and mRNA levels of NF-κB increased with benzene exposure. Inspiringly, shikonin alleviated benzene-induced male reproductive damage by targeting m6A-modified NF-κB in mice testes. Our study provides new insights into molecular mechanisms of RNA m6A modification in benzene-induced reproductive injury and directions to find potential drugs for the treatment of male infertility.
Insights
Benzene exposure harms male fertility via oxidative stress and inflammation. Shikonin offers a potential treatment by targeting RNA modifications involved in NF-κB signaling.
Area of Science:
- Toxicology
- Reproductive Biology
- Molecular Biology
Background:
- Benzene exposure is a known cause of reproductive toxicity, primarily through oxidative damage.
- The precise molecular mechanisms underlying benzene-induced testicular damage and effective therapeutic interventions are not fully elucidated.
Purpose of the Study:
- To investigate the mechanisms of benzene-induced testicular damage.
- To explore the role of RNA methylation in benzene toxicity.
- To identify potential therapeutic agents for male reproductive injury.
Main Methods:
- Mice were exposed to benzene (150 mg/kg) for four weeks.
- Testicular damage was assessed via coefficients, semen analysis, and histology.
- In vitro studies used GC-2 cells treated with 1,4-BQ.
- Gene expression and RNA methylation (m6A) were analyzed.
- Shikonin's therapeutic effect was evaluated.
Main Results:
- Benzene exposure led to decreased testicular coefficients, abnormal semen parameters, and intraepithelial vacuolation.
- Activation of Keap1/Nrf2 and NF-κB pathways, increased ROS, and apoptosis were observed.
- Benzene altered expression of RNA methylation regulators (Mettl3, Alkbh5, Ythdc2) and increased m6A modification and NF-κB mRNA levels.
- Shikonin treatment ameliorated benzene-induced testicular damage.
Conclusions:
- Benzene induces male reproductive toxicity through oxidative stress, inflammation, and apoptosis, involving Keap1/Nrf2 and NF-κB pathways.
- RNA m6A modification plays a critical role in benzene-induced male reproductive injury.
- Shikonin demonstrates therapeutic potential by targeting m6A-modified NF-κB, offering a novel strategy for treating benzene-induced male infertility.
