Sperm Rhoa m6A modification mediates intergenerational transmission of paternally acquired hippocampal neuronal senescence and cognitive deficits after combined exposure to environmental cadmium and high-fat diet in mice

Authors：Zhang, J., Xiong, Y. W., Tan, L. L., Zheng, X. M., Zhang, Y. F., Ling, Q., Zhang, C., Zhu, H. L., Chang, W., & Wang, H

Source：J Hazard Mater. 2023 Jun 19;458:131891

DOI: 10.1016/j.jhazmat.2023.131891

Abstract：Little is currently known about the effect and mechanism of combined paternal environmental cadmium (Cd) and high-fat diet (HFD) on offspring cognitive ability. Here, using in vivo model, we found that combined paternal environmental Cd and HFD caused hippocampal neuronal senescence and cognitive deficits in offspring. MeRIP-seq revealed m6A level of Rhoa, a regulatory gene of cellular senescence, was significantly increased in combined environmental Cd and HFD-treated paternal sperm. Interestingly, combined paternal environmental Cd and HFD markedly enhanced Rhoa mRNA, its m6A and reader protein IGF2BP1 in offspring hippocampus. STM2457, the inhibitor of m6A modification, markedly mitigated paternal exposure-caused the elevation of hippocampal Rhoa m6A, neuronal senescence and cognitive deficits in offspring. In vitro experiments, Rhoa siR significantly reversed mouse hippocampal neuronal senescence. Igf2bp1 siR obviously reduced the level and stability of Rhoa in aging mouse hippocampal neuronal cells. In conclusion, combined paternal environmental Cd and HFD induce offspring hippocampal neuronal senescence and cognitive deficits by promoting IGF2BP1-mediated Rhoa stabilization in offspring hippocampus via elevating Rhoa m6A in paternal sperm.

Keywords: Cadmium; Cognitive ability; High-fat diet; Paternal; Sperm m6A.

中文摘要：父亲环境镉(Cd)暴露与高脂饮食(HFD)联合对后代认知功能的影响及其机制目前尚不清楚。本研究通过体内模型发现，父亲环境Cd暴露和HFD联合作用可导致后代海马神经元衰老和认知缺陷。MeRIP-seq结果显示，环境Cd和HFD联合处理的父亲精子中细胞衰老调控基因Rhoa的m6A水平显著升高。有趣的是，父亲环境Cd暴露和HFD组合显著增强了子代海马Rhoa mRNA、其m6A和读取器蛋白IGF2BP1。STM2457是m6A修饰抑制剂，可显著减轻父亲暴露导致的后代海马Rhoa m6A升高、神经元衰老和认知缺陷。体外实验中，Rhoa siR显著逆转小鼠海马神经元衰老。Igf2bp1 siR明显降低了衰老小鼠海马神经元细胞中Rhoa的水平和稳定性。综上所述，父亲环境Cd暴露和HFD联合通过提高父亲精子中Rhoa m6A，促进igf2bp1介导的子代海马Rhoa稳定，从而诱导子代海马神经元衰老和认知缺陷。

关键词：镉;认知能力;高脂肪饮食;父亲的;精子m6A。