基于FTO介导m6A修饰探讨甜菜碱在氟致子代学习记忆损伤中的作用及机制研究

氟中毒存在传代效应，如何预防氟中毒患者后代智力损伤是氟中毒现阶段防治的重要问题。孕期补充甲基供体营养素是减轻或消除环境刺激导致后代表观基因组失调的潜在预防措施。研究报道甜菜碱作为高效甲基供体可纠正环境因素导致的RNA甲基化不足，增加m6A修饰水平，以调控相关基因表达，从而改善多种毒物诱导的学习记忆障碍。课题组前一国家自然科学基金人群数据分析发现甲基供体营养素中甜菜碱对氟中毒保护作用最强，但甜菜碱能否预防氟中毒所致子代学习记忆损伤及作用机制尚不清楚。因此，本项目采用动物实验观察孕期及哺乳期甜菜碱补充对氟中毒大鼠子代学习记忆损伤的预防作用，检测仔鼠特定基因m6A修饰及BDNF/ERK/CREB通路关键基因mRNA与蛋白表达；通过原代海马神经细胞、N27细胞、FTO沉默和过表达细胞模型进一步阐明其表观遗传机制；为氟中毒跨代遗传的营养预防提供理论依据，这对促进氟病区人口优生优育具有重要意义。

There were generational effects of fluoride on the development of the offspring. How to prevent the intellectual reduction of fluorosis patient’s children is an important problem in the current prevention and control of fluorosis. Supplementation with methyl-donor nutrients during pregnancy is a potential preventive measure to reduce or eliminate alteration of epigenome induced by environment. Betaine, a highly efficient methyl-donor can improve learning and memory disorders induced by various poisons due to it rectified the deficiency of RNA methylation with dose-dependent increasing m6A levels to regulate expression of related genes. Analysis of the previous National Natural Science Foundation project showed that betaine had the strongest protective effect on fluorosis in all of methyl-donor nutrients. However, it is unclear whether betaine can prevent learning and memory damage of fluorosis rat offspring and the underlying mechanisms. Therefore, the objectives of present study are to observe the preventive effect of supplementation with betaine during gestation and lactation rats with fluorosis on the learning and memory impairment of their offspring. Furthermore, we will determine the m6A modification in hippocampus and specific gene, and mRNA and protein expression of key genes in BDNF/ERK/CREB pathway. Epigenetic mechanisms will be further elucidated by primary hippocampal neurons, N27 cell lines, silenced-FTO and overexpressed-FTO N27 cells model. It is of great significance to provide theoretical basis for the nutritional prevention of generational inheritance of fluorosis and to promote the healthy birth and good postnatal care in fluorosis areas.