Abstract：
Bisphenol F (BPF) has been extensively utilized in daily life, which brings new hazards to male reproductive health. However, the specific functional mechanism is still unclear. Both cell and animal models were utilized for exploring the role of RNA methylation and ferroptosis and its underlying mechanisms in male reproductive injury induced by BPF. In animal model, BPF severely destroyed the integrity of the blood-testis barrier (BTB) and induced ferroptosis. Furthermore, BPF significantly affected the barrier function of TM4 cells and promoted ferroptosis. Importantly, ChIP assays revealed that BPF inhibited AR transcriptional regulation of FTO and FTO expression was downregulated in TM4 cells. Overexpression of FTO prevented the impairment of BTB by inhibiting ferroptosis in TM4 cells. Mechanistically, FTO could significantly down-regulate the m6A modification level of TfRc and SLC7A11 mRNA through MeRIP experiment. RIP experiments showed that YTHDF1 can bind to TfRc mRNA and promote its translation while YTHDF2 could bind to SLC7A11 mRNA and reduce its mRNA stability. Therefore, our results suggest that FTO plays a key role in BPF induced male reproductive toxicity through YTHDF1-TfRc axis and YTHDF2-SLC7A11 axis and may provide new ideas and methods for the prevention and treatment of male reproductive diseases associated with environmental pollutants.
摘要：
双酚F(BPF)在日常生活中得到了广泛的应用,这给男性生殖健康带来了新的危害。然而,具体的功能机制尚不清楚。利用细胞和动物模型来探索RNA甲基化和铁凋亡的作用及其在BPF诱导的男性生殖损伤中的潜在机制。在动物模型中,BPF严重破坏了血睾丸屏障（BTB）的完整性并诱导了铁凋亡。此外，BPF显著影响TM4细胞的屏障功能并促进铁凋亡。重要的是,ChIP实验表明，BPF抑制了FTO的AR转录调节，并且在TM4细胞中FTO表达下调。FTO的过表达通过抑制TM4细胞中的铁凋亡来防止BTB的损伤。机械上,通过MeRIP实验，FTO可以显著下调TfRc和SLC7A11mRNA的m6A修饰水平。RIP实验表明，YTHDF1可以与TfRcmRNA结合并促进其翻译，而YTHDF2可以与SLC7A11mRNA结合并降低其mRNA稳定性。因此,我们的结果表明，FTO通过YTHDF1-TfRc轴和YTHDF2-SLC7A11轴在BPF引起的生殖毒性中起关键作用，可能为预防和治疗与环境污染物相关的男性生殖疾病提供新的思路和方法。
