Paternal nicotine exposure promotes hepatic fibrosis in offspring

• Published in: Toxicology letters Vol. 343; pp. 44 - 55
• Main Authors: Zhang, Dong, Dai, Jingbo, Zhang, Meixing, Xie, Yilin, Cao, Yong, He, Guang, Xu, Wangjie, Wang, Lianyun, Qiao, Zhiguang, Qiao, Zhongdong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2021
• Subjects: Animals; Down-Regulation; Epigenesis, Genetic; Gene Expression Regulation - drug effects; Hepatic fibrosis; Intergenerational transmission; Liver Cirrhosis - chemically induced; Male; Methylation; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Nicotine; Nicotine - toxicity; Nicotinic Agonists - toxicity; Paternal Exposure; RNA, Messenger - genetics; RNA, Messenger - metabolism; Wnt pathway; Wnt4 Protein - genetics; Wnt4 Protein - metabolism; Hepatic fibrosis; Intergenerational transmission; Methylation; Wnt pathway; Nicotine
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2021.02.015

[Display omitted] •Our study firstly confirmed that paternal nicotine exposure promotes hepatic fibrosis in offspring.•Our study explained the effect of nicotine on offspring via epigenetics.•Our results enriched the understanding of the effects of paternal nicotine exposure to offspring. Paternal nicotine exposure can alter phenotypes in future generations. The aim of this study is to explore whether paternal nicotine exposure affects the hepatic repair to chronic injury which leads to hepatic fibrosis in offspring. Our results demonstrate that nicotine down regulates mmu-miR-15b expression via the hyper-methylation on its CpG island shore region in the spermatozoa. This epigenetic modification imprinted in the liver of the offspring. The decreased mmu-miR-15b promotes the expression of Wnt4 and activates the Wnt pathway in the offspring mice liver. The activation of the Wnt pathway improves the activation and proliferation of hepatic stellate cells (HSCs) leading to liver fibrosis. Moreover, the Wnt pathway promotes the activation of the TGF-β pathway and the two pathways cooperate to promote the transcription of extracellular matrix (ECM) genes. In conclusion, this study found that nicotine promotes hepatic fibrosis in the offspring via the activation of Wnt pathway by imprinting the hyper-methylation of mmu-miR-15b.