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FTO-Nrf2 axis regulates bisphenol F-induced leydig cell toxicity in an m6A-YTHDF2-dependent manner
Shi-Meng Zhou1, Jing-Zhi Li2, Hong-Qiang Chen3
1Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China.
Abstract:
Studies have shown that Bisphenol F (BPF) as an emerging bisphenol pollutant also has caused many hazards to the reproductive systems of humans and animals. However, its specific mechanism is still unclear. The mouse TM3 Leydig cell was used to explore the mechanism of BPF-induced reproductive toxicity in this study. The results showed BPF (0, 20, 40 and 80 μM) exposure for 72 h significantly increased cell apoptosis and decreased cell viability. Correspondingly, BPF increased the expression of P53 and BAX, and decreased the expression of BCL2. Moreover, BPF significantly increased the intracellular ROS level in TM3 cells, and significantly decreased oxidative stress-related molecule Nrf2. BPF decreased the expression of FTO and YTHDF2, and increased the total cellular m6A level. ChIP results showed that AhR transcriptionally regulated FTO. Differential expression of FTO revealed that FTO reduced the apoptosis rate of BPF-exposed TM3 cells and increased the expression of Nrf2, MeRIP confirmed that overexpression of FTO reduced the m6A of Nrf2 mRNA. After differential expression of YTHDF2, it was found that YTHDF2 enhanced the stability of Nrf2, and RIP assay showed that YTHDF2 was bound to Nrf2 mRNA. Nrf2 agonist enhanced the protective effect of FTO on TM3 cells exposure to BPF. Our study is the first to demonstrate that AhR transcriptionally regulated FTO, and then FTO regulated Nrf2 in a m6A-modified manner through YTHDF2, thereby affecting apoptosis in BPF-exposed TM3 cells to induce reproductive damage. It provides new insights into the importance of FTO-YTHDF2-Nrf2 signaling axis in BPF-induced reproductive toxicity and provided a new idea for the prevention of male reproductive injury.
Insights
Bisphenol F (BPF) exposure harms reproductive systems by increasing cell apoptosis via the AhR-FTO-YTHDF2-Nrf2 pathway. This study reveals how BPF induces male reproductive damage, offering insights for prevention.
Area of Science:
- Environmental Toxicology
- Reproductive Biology
- Molecular Mechanisms
Background:
- Bisphenol F (BPF) is an emerging pollutant with known reproductive toxicity.
- The precise molecular mechanisms underlying BPF-induced reproductive damage remain largely unknown.
- Understanding these mechanisms is crucial for developing effective prevention strategies.
Purpose of the Study:
- To elucidate the specific molecular pathways involved in Bisphenol F (BPF)-induced reproductive toxicity.
- To investigate the role of the FTO-YTHDF2-Nrf2 signaling axis in BPF toxicity.
- To identify potential therapeutic targets for mitigating BPF-induced male reproductive injury.
Main Methods:
- Utilized mouse TM3 Leydig cells for in vitro toxicity assessments.
- Assessed cell apoptosis, viability, and reactive oxygen species (ROS) levels.
- Employed techniques including ChIP, MeRIP, and RIP assays to investigate molecular interactions and modifications.
- Examined the expression levels of key proteins and mRNA, including P53, BAX, BCL2, Nrf2, FTO, and YTHDF2.
Main Results:
- BPF exposure significantly increased apoptosis and decreased viability in TM3 Leydig cells.
- BPF elevated ROS levels and downregulated the oxidative stress regulator Nrf2.
- AhR was found to transcriptionally regulate FTO, which in turn modulated Nrf2 expression via m6A modification and YTHDF2 binding.
- FTO and YTHDF2 were identified as key mediators in the protective effects against BPF-induced apoptosis and oxidative stress.
Conclusions:
- This study reveals a novel mechanism where AhR-regulated FTO influences Nrf2 via m6A modification and YTHDF2, impacting apoptosis in BPF-exposed cells.
- The FTO-YTHDF2-Nrf2 signaling axis plays a critical role in BPF-induced reproductive toxicity.
- These findings provide new insights into male reproductive injury prevention strategies targeting this pathway.
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