Wei Xiaoyu, Zhang Zhonghao, Gu Yayun, Zhang Rong, Huang Jie, Li Feng, He Yuanlin, Lu Shuai, Wu Yifei, Zeng Wentao, Liu Xiaorui, Liu Chenzi, Liu Jinyi, Ao Lin, Shi Fuquan, Chen Qing, Lin Yuan, Du Jiangbo, Jin Guangfu, Xia Yankai, Ma Hongxia, Zheng Yuxin, Huo Ran, Cao Jia, Shen Hongbing, Hu Zhibin
State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Cell Discov. 2024 Apr 23;10(1):44. doi: 10.1038/s41421-024-00657-0.
Exposure to PM, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3'-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.
暴露于细颗粒物（PM，一种有害的空气污染类型）与男性生殖健康受损有关；然而，这种暴露是否会对男性生育能力产生跨代影响仍不清楚。在此，我们旨在研究父亲暴露于实际环境中的PM对雄性后代生殖健康的影响。我们观察到，父亲暴露于实际环境中的PM会以性别选择性的方式导致跨代原发性性腺功能减退，并且我们还通过使用外部模型证实了这一表型。从机制上来说，我们已经确定了在介导这些跨代效应中起关键作用的小RNA（sRNA）。具体而言，F0代PM精子中存在的miR6240和piR016061分别通过靶向Lhcgr和Nsd1来调节代际传递。我们还发现，piR033435和piR006695通过与Tet1 mRNA的3'非翻译区结合间接调节F1代PM精子甲基化。Tet1表达的降低导致包括Lhcgr和Gnas在内的几个睾酮合成基因的高甲基化，损害了睾丸间质细胞功能，并最终导致跨代原发性性腺功能减退。我们的研究结果为父亲PM暴露对生殖健康的跨代影响的潜在机制提供了见解，突出了sRNA在介导这些影响中所起的关键作用。这些发现强调了父亲孕前干预在减轻环境污染物对生殖健康的不利影响方面的重要性。
