METTL3-m6A-SIRT1 axis affects autophagic flux contributing to PM2.5-induced inhibition of testosterone production in Leydig cells

• Published in: The Science of the total environment 2024-03, Vol.918, p.170701-170701, Article 170701
• Main Authors: Jiang, Lianlian, Lin, Xiaojun, Jiang, Jinchen, Qiu, Chong, Zheng, Shaokai, Zhao, Nannan, Shu, Zhenhao, Qian, Yinyun, Qiu, Lianglin
• Format: Article
• Language: English
• Subjects: Autophagy; PM2.5; RNA m6A methylation; SIRT1; Testosterone production
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2024.170701

Epidemiological studies have found that long-term inhalation of PM2.5 is closely related to spermatogenesis disorders and infertility, but the underlying molecular mechanism is still unidentified. Testosterone, an essential reproductive hormone produced by Leydig cells, whose synthesis is disrupted by multiple environmental pollutants. In the current study, we explored the role of METTL3-m6A-SIRT1 axis-mediated abnormal autophagy in PM2.5-induced inhibition of testosterone production in in vivo and in vitro models. Our in vivo findings shown that long-term inhalation of PM2.5 decreased sperm count, increased sperm deformity rates, and altered testicular interstitial morphology accompanied by reduced testosterone in serum and testes. Further, data from the in vitro model displayed that exposure to PM2.5 caused an increase in m6A modification and METTL3 levels, followed by a decrease in testosterone levels and autophagy dysfunction in Leydig cells. The knockdown of METTL3 promotes autophagy flux and testosterone production in Leydig cells. Mechanistically, PM2.5 increased METTL3-induced m6A modification of SIRT1 mRNA in Leydig cells, bringing about abnormal autophagy. Subsequently, administration of SRT1720 (a SIRT1 activator) enhanced autophagy and further promoted testosterone biosynthesis. Collectively, our discoveries indicate that METTL3-m6A-SIRT1 axis-mediated autophagic flux contributes to PM2.5-induced inhibition of testosterone biosynthesis. This research offers a novel viewpoint on the mechanism of male reproductive injury following PM2.5 exposure. [Display omitted] •PM2.5 induces METTL3-mediated m6A methylation changes in testis and Leydig cells.•METTL3 increases the methylation level of m6A in SIRT1, thus reducing its stability.•Autophagy flux is positively correlated with SIRT1 level.•Autophagy flux regulated by SIRT1 is related to PM2.5-induced inhibition of testosterone production in Leydig cells.