Reticulophagy promotes EMT-induced fibrosis in offspring’s lung tissue after maternal exposure to carbon black nanoparticles during gestation by a m5C-dependent manner

Abstract

Accumulating evidence indicates that maternal exposure to carbon black nanoparticles (CBNPs) during gestation can induce multiple system abnormalities in offspring, whereas its potential mechanism in respiratory disease is still largely unknown. In order to explore the effect of maternal exposure to CBNPs on offspring’s lung and latent pathogenesis, we respectively established in vivo model of pregnant rats exposed to CBNPs and ex vivo model of lung epithelial cells treated with pups’ serum of pregnant rats exposed to CBNPs. After maternal exposure to CBNPs, epithelial-mesenchymal transition (EMT) and fibrosis levels increased as a result of DDRGK1-mediated reticulophagy upregulated in offspring’s lung. DDRGK1 as FAM134B’s cargo bound with FAM134B to mediate reticulophagy. Transcription factor “SP1” positively regulated DDRGK1 gene expression by binding to its promoter. Furthermore, the upregulation of NSUN2 elevated m⁵C methylation of SP1 mRNA and the protein level of SP1 subsequently increased through Ybx1 recognizing and stabilizing m⁵C-methylated SP1 mRNA, followed by the increased levels of reticulophagy and fibrosis in lung epithelial cells treated with offspring’s serum of matrix exposed to CBNPs during gestation. In conclusion, NSUN2/Ybx1/m⁵C-SP1 axis promoted DDRGK1-mediated reticulophagy, which played an important role in EMT-induced fibrosis in offspring’s lung tissue after maternal exposure to CBNPs during gestation.