Shen Jinghua, Gao Jingjing, Wang Xinyi, Yan Dongying, Wang Ying, Li Hong, Chen Dawei, Wu Jie
Department of Occupational and Environmental Health, School of Public Health, Jinzhou Medical University, Jinzhou, Liaoning, PR China.
School of Public Health, Jinzhou Medical University, Jinzhou, Liaoning, PR China.
Food Chem Toxicol. 2025 Feb;196:115243. doi: 10.1016/j.fct.2025.115243. Epub 2025 Jan 7.
Flame retardant polybrominated diphenyl ethers (PBDEs) accumulate in human bodies through food and dust ingestion, and cause neurobehavioral deficits with obscure mechanism. We aimed to investigate NMDAR-CaMKⅡγ-mediated synapse-to-nuclear communication involved in BDE-209-induced cognitive impairment, and alleviation from exogenous melatonin. Decreased NMDAR subunits GluN2A and 2B, autophosphorylation of CaMKⅡα, and postsynaptic GluA1 trafficking were observed in the hippocampus of juvenile rats after maternal BDE-209 exposure. Moreover, nuclear shuttling of CaMKⅡγ with CaM, as well as downstream nuclear p-CaMKIV and p-CREB-dependent genes (Bdnf, c-Fos, Arc) expression were all causally down-regulated. These resulted in less dendritic spines in CA1 area and poor spatial learning and memory. Importantly, elevated miR-219a-5p in transcriptome sequencing was identified together with its targets Grin2b and Camk2g mRNA, further elucidated the reduction in GluN2B and CaMKⅡγ protein. These changes on synaptic plasticity caused by BDE-209 were reversed correspondingly under pretreatment of melatonin, partially via miR-219a inhibition. Collectively, our findings suggest that synaptonuclear signaling alterations potentially mediated neurobehavioral deficits induced by early-life BDE-209 exposure and the neuroprotection from melatonin, therefore provided a novel perspective for prevention.
阻燃多溴二苯醚（PBDEs）通过食物和灰尘摄入在人体中蓄积，并导致神经行为缺陷，但其机制尚不清楚。我们旨在研究NMDAR-CaMKⅡγ介导的突触到核的通讯在BDE-209诱导的认知障碍中的作用，以及外源性褪黑素的缓解作用。在母体暴露于BDE-209的幼年大鼠海马中，观察到NMDAR亚基GluN2A和2B减少、CaMKⅡα的自磷酸化以及突触后GluA1的转运。此外，CaMKⅡγ与CaM的核穿梭以及下游核p-CaMKIV和p-CREB依赖性基因（Bdnf、c-Fos、Arc）的表达均被下调。这些导致CA1区树突棘减少以及空间学习和记忆能力差。重要的是，在转录组测序中发现miR-219a-5p升高及其靶标Grin2b和Camk2g mRNA，进一步阐明了GluN2B和CaMKⅡγ蛋白的减少。BDE-209引起的这些突触可塑性变化在褪黑素预处理下相应地得到逆转，部分是通过抑制miR-219a实现的。总的来说，我们的研究结果表明，突触-核信号改变可能介导了早期BDE-209暴露引起的神经行为缺陷以及褪黑素的神经保护作用，因此为预防提供了一个新的视角。
