Background

To reveal the underling molecular mechanism in brain damage induced by chronic fluorosis, the neurotoxicity and its correlation were investigated by transcriptomics and proteomics.

Methods

Sprague-Dawley rats were treated with fluoride at different concentrations (0, 5, 50 and 100 ppm, prepared by NaF) for 3 months. Spatial learning and memory were evaluated by Morris water maze test; neuronal morphological change in the hippocampus was observed using Nissl staining; and the level of oxidative stress including reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by biological methods. The high-throughput transcriptome sequencing (RNA-Seq) and tandem mass tag (TMT) proteomic sequencing were performed to detect the expression of differentially expressed genes and proteins, respectively.

Results

The results showed that compared with control group, rats exposed to high-dose fluoride exhibited declined abilities of learning and memory, decreased SOD activity and increased ROS and MDA levels, with lighter colored Nissl bodies. A total of 28 important differentially expressed genes (DEGs) were screened out by transcriptomics. Then, functional enrichment analyses showed that upregulated proteins enriched in cellular transport, while downregulated proteins enriched in synapse-related pathways. Thirteen corresponding DEGs and DAPs (cor-DEGs-DAPs) were identified by differential expressions selected with positively correlated genes/proteins, most of which were related to neurodegenerative changes and oxidative stress response.

Conclusion

These results provide new omics evidence that rats chronically exposed to high-dose fluoride can induce neurotoxicity in the brains through changes in the cholinergic pathway and oxidative stress.

中文翻译：

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综合转录组学和蛋白质组学分析表明慢性氟中毒大鼠的神经毒性可能与胆碱能通路改变和氧化应激有关

背景

为了揭示慢性氟中毒所致脑损伤的潜在分子机制，通过转录组学和蛋白质组学研究了神经毒性及其相关性。

方法

用不同浓度（0、5、50 和 100 ppm，由 NaF 制备）的氟化物处理 Sprague-Dawley 大鼠 3 个月。空间学习记忆通过Morris水迷宫测验进行评价；Nissl染色观察海马神经元形态学变化；并通过生物学方法检测氧化应激水平，包括活性氧（ROS）、丙二醛（MDA）和超氧化物歧化酶（SOD）。进行高通量转录组测序（RNA-Seq）和串联质量标签（TMT）蛋白质组测序，分别检测差异表达基因和蛋白质的表达。

结果

结果表明，与对照组相比，暴露于高剂量氟化物的大鼠表现出学习和记忆能力下降，SOD活性降低，ROS和MDA水平升高，尼氏体颜色较浅。通过转录组学共筛选出28个重要的差异表达基因（DEGs）。然后，功能富集分析表明，上调的蛋白质富含细胞转运，而下调的蛋白质富含突触相关通路。通过选择具有正相关基因/蛋白质的差异表达鉴定了 13 个相应的 DEGs 和 DAPs（cor-DEGs-DAPs），其中大部分与神经退行性变化和氧化应激反应有关。

结论

这些结果提供了新的组学证据，表明长期暴露于高剂量氟化物的大鼠可以通过胆碱能通路和氧化应激的变化在大脑中诱导神经毒性。