生命早期暴露饥荒对成年期心血管代谢危险因素的跨代影响及表观遗传机制研究

Controlling the cardiometabolic risk factors is considered to be the best strategy to efficiently prevent the incidence of cardiovascular disease. Recently, rodent studies showed that the long-term effects of early-life exposure to under-nutrition on cardiometabolic risk factors may not be limited to one generation even in the absence of further environmental stressors. However, there is as yet no direct human study that has examined whether any prenatal effects on cardiometabolic risk may transmit to subsequent generations and the underlying mechanisms involved in for any potential trans-generational effects. In this project, we firstly established the Chinese famine cohort based on family, in which two generations (i.e. the parents (F1) who exposed to famine in early-life period and their offspring (F2)) were involved. Secondly, using this cohort, we will clarify the trans-generational effects of early-life exposure to famine on cardiometabolic risk factors in adulthood in two consecutive generations and study the interactive effects of early-life exposure to famine and dietary pattern in adulthood on cardiometabolic risk factors in two consecutive generations; compare the trans-generational effects of maternal and paternal exposure as well as one parent and both parents exposure to famine on offspring cardiometabolic risk factors in adulthood; and explore whether the abovementioned trans-generational effects of early-life exposure to famine on cardiometabolic risk factors in adulthood are mediated by DNA methylation. Thirdly, we will investigate whether the prenatal nutrient deprivation–induced adverse effects on cardiometabolic risk factors in two consecutive generations can be reversed with the introduction of early postnatal calorie restriction in a mice model of intra-uterine nutrition restriction. Finally, we will propose the specific prevention and control measures of cardiovascular risk factors from the view of life course and then to curb the highly epidemic cardiovascular diseases in China.

控制心血管代谢危险因素是有效防控心血管疾病的最佳策略。动物研究表明，生命早期所暴露的营养状况对成年后诸多心血管代谢危险因素的影响不仅局限于一代，而是可能存在跨代影响效应，但尚无法在人群研究中直接验证，且机制不明。本项目中，我们首次建立了以家庭为研究单位的中国饥荒队列，其中包括生命早期暴露饥荒的父母（F1代）及其子女（F2代）；利用该队列，拟分析F1生命早期暴露饥荒对F1和F2成年后心血管代谢危险因素的跨代影响，以及F1和F2成年期营养状况在其中发挥的调节作用；比较母系暴露和父系暴露以及父母一方暴露和双方暴露，对后代成年期心血管代谢危险因素的影响能力是否存在差异；从全基因组水平研究在上述跨代影响过程中起中介作用的DNA甲基化位点，进行表观遗传机制探讨；在动物实验中，进一步探讨出生后适当的膳食干预是否能阻断或逆转上述跨代影响。最终，从整个生命历程视角提出适合我国国情的心血管疾病防控方案。

控制心血管代谢危险因素是有效防控心血管疾病的最佳策略。动物研究表明，生命早期所暴露的营养状况对成年后诸多心血管代谢危险因素的影响不仅局限于一代，而是可能存在跨代影响效应，但尚无法在人群研究中直接验证，且机制不明。本项目中，我们首次建立了以家庭为研究单位的中国饥荒绥化队列，并整合中国健康与营养调查（CHNS）队列数据。在绥化队列中，我们发现，在校正相关混杂因素后，F1代生命早期暴露饥荒组患高血糖的风险是非暴露组的1.93倍（OR: 1.93 [1.51–2.48]）; 而且这种饥荒效应在F2代仍然存在，父母出生前暴露饥荒，尤其是父母双方都暴露饥荒组患糖尿病的风险是父母双方均未暴露饥荒组的2.02倍（OR: 2.02 [1.12–3.66]）。对CHNS队列数据的分析显示，在F1代中，饥荒暴露组BMI、SBP和DBP的随年龄增加速度比非暴露组更快，而且饥荒暴露对男性的影响大于女性；在F2代中这种趋势仍然存在。中介分析结果显示，生命早期暴露饥荒对血糖和血压的跨代影响部分通过INSIGF和LEP基因的甲基化改变所介导的。我们进一步在动物实验中研究了孕期低蛋白饮食干预对全基因组DNA甲基化的跨代影响。结果发现，孕期低蛋白饮食干预影响子代肝脏、白色脂肪和棕色脂肪的DNA甲基化谱，而且部分位点的DNA甲基化改变可以传递到下一代，这些位点主要存在于与发育和代谢、免疫、生物钟和甲基化反应相关的基因。从理论上而言，这一研究为进一步阐明人类的跨代表观继承现象提供了新的突破口；从临床实践的角度看，这一发现证实了生命早期的发育环境对成年期健康的深远影响，支持从全生命周期的视角制定心血管代谢疾病的防控策略。