青少年环境镉和高脂饮食联合暴露通过Larp7 m6A介导的SIRT6抑制诱导认知能力下降

Adolescent co-exposure to environmental cadmium and high-fat diet induces cognitive decline via Larp7 m6A-mediated SIRT6 inhibition          

青少年环境镉和高脂饮食联合暴露通过Larp7 m6A介导的SIRT6抑制诱导认知能力下降

Authors: Zhang J, Xiong YW, Zhu HL, Tan LL, Zhou H, Zheng XM, Zhang YF, Chang W, Xu DX, Wei T, Guan SZ, Wang H.

Source：J Hazard Mater. 2024 Sep 5;476:135159. doi: 10.1016/j.jhazmat.2024.135159.

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.

Keywords: Cadmium; Cognitive function; High-fat diet; LARP7; SIRT6.

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。在这里，使用组合暴露模型，我们发现显着的认知能力下降，海马神经元损伤，神经元衰老的小鼠暴露于镉（Cd）和高脂饮食（HFD）在青春期。此外，我们观察到共同暴露小鼠的海马中Sirtuin 6（SIRT6）表达的显著下调。特异性SIRT6激活剂UBCS 039可明显逆转上述不良反应。进一步研究发现，共暴露可明显降低小鼠海马神经元LARP7的水平，破坏LARP7与SIRT6之间的相互作用，最终降低SIRT6的表达。Larp 7的过表达逆转了小鼠海马神经元细胞中联合暴露诱导的SIRT 6下降和衰老。此外，结果显示在用组合危害处理的小鼠海马神经元细胞中Larp7 m6A和YTH结构域家族蛋白2（YTHDF2）的水平显著升高。Ythdf2短干扰RNA、RNA免疫沉淀和RNA稳定性测定进一步证明，在组合暴露下，Ythdf2介导Larp7 mRNA的降解。总的来说，青少年共同暴露于镉和HFD导致海马衰老和认知能力下降的小鼠通过抑制LARP7介导的SIRT6表达的m6A依赖的方式。

关键词：镉;认知功能;高脂饮食; LARP 7; SIRT 6