Abstract：
The effects and underlying mechanisms of adolescent exposure to combined environmental hazards on cognitive function remain unclear. Here, using a combined exposure model, we found significant cognitive decline, hippocampal neuronal damage, and neuronal senescence in mice exposed to cadmium (Cd) and high-fat diet (HFD) during adolescence. Furthermore, we observed a significant downregulation of Sirtuin 6 (SIRT6) expression in the hippocampi of co-exposed mice. UBCS039, a specific SIRT6 activator, markedly reversed the above adverse effects. Further investigation revealed that co-exposure obviously reduced the levels of La ribonucleoprotein 7 (LARP7), disrupted the interaction between LARP7 and SIRT6, ultimately decreasing SIRT6 expression in mouse hippocampal neuronal cells. Overexpression of Larp7 reversed the combined exposure-induced SIRT6 decrease and senescence in mouse hippocampal neuronal cells. Additionally, the results showed notably elevated levels of Larp7 m6A and YTH domain family protein 2 (YTHDF2) in mouse hippocampal neuronal cells treated with the combined hazards. Ythdf2 short interfering RNA, RNA immunoprecipitation, and RNA stability assays further demonstrated that YTHDF2 mediated the degradation of Larp7 mRNA under combined exposure. Collectively, adolescent co-exposure to Cd and HFD causes hippocampal senescence and cognitive decline in mice by inhibiting LARP7-mediated SIRT6 expression in an m6A-dependent manner.
摘要：
青少年暴露于综合环境危害对认知功能的影响和潜在机制尚不清楚。这里,使用组合曝光模型，我们发现了显著的认知能力下降，海马神经元损伤，和青春期暴露于镉（Cd）和高脂饮食（HFD）的小鼠的神经元衰老。此外，我们观察到Sirtuin6(SIRT6)在共同暴露小鼠海马中的表达显著下调。UBCS039，一种特定的SIRT6激活剂，明显逆转了上述不良反应。进一步的调查显示，共同暴露明显降低了La核糖核蛋白7（LARP7）的水平，破坏了LARP7和SIRT6之间的相互作用，最终降低了小鼠海马神经元细胞中SIRT6的表达。Larp7的过表达逆转了小鼠海马神经元细胞中联合暴露诱导的SIRT6降低和衰老。此外,结果显示，在联合危害处理的小鼠海马神经元细胞中，Larp7m6A和YTH结构域家族蛋白2（YTHDF2）的水平显着升高。Ythdf2短干扰RNA，RNA免疫沉淀，和RNA稳定性测定进一步证明YTHDF2在联合暴露下介导Larp7mRNA的降解。总的来说，青少年共同暴露于Cd和HFD通过以m6A依赖性方式抑制LARP7介导的SIRT6表达而导致小鼠海马衰老和认知功能下降。
