Parental dietary vitamin B12 and folate deficiency: defining epigenetic mechanisms underlying offspring cardio-metabolic health

父母膳食维生素 B12 和叶酸缺乏：定义后代心脏代谢健康的表观遗传机制

• 批准号: 2746121
• 金额: --
• 依托单位: Nottingham Trent University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2746121
• 关键词: Parental; dietary; vitamin; B12; folate

Background: Human epidemiological data and animal studies indicate that poor parental diet around the time of conception increases the risk for cardio-metabolic disease in offspring over multiple generations. These observations highlight epigenetic factors as one potential mechanism linking parental diet with the programmed ill-health of their offspring. Whilst post-conception consequences of general dietary imbalances of either parent in isolation has been established, there is little information on the interactive impact of both parental diets on offspring health, and no data on the effects of disturbances to one-carbon metabolism; which we have demonstrated is central to the epigenetic regulation of embryonic development and offspring wellbeing.Hypothesis: Dietary deficiencies in vitamin B12 and folate has been shown to disturb one-carbon metabolism in parents, leading to epigenetic modifications in offspring, thereby perturbing their development, health and well-being. We hypothesise that if both parents consume the same sub-optimal, low B12/folate diet (which is highly likely to occur in human couples), this will have a greater impact on offspring development and well-being than for either parent alone. Parentally inherited epigenetic modifications driving differential patterns of gene expression, tissue function and offspring growth will underlie these effects. Aims: In a factorially arranged design, we will define the parental-specific contribution to offspring health through feeding male and female mice either a low B12/folate diet or a control diet, for 7 weeks prior to mating, to ensure all stages of gamete development and maturation are exposed to the diets. Males and females will then be mated in combination to determine the specific impact of (i) paternal low one-carbon diet alone; (ii) maternal low one-carbon diet alone, (iii) combined parental low one-carbon diet or (iv) combined control parental diet. Approach: Throughout the feeding period, samples of maternal and paternal blood will be collected and assayed for metabolic endpoints of one-carbon metabolism (by LC-MS/MS (Antonysunil lab, NTU).

背景：人类流行病学数据和动物研究表明，父母在怀孕期间的不良饮食会增加后代多代患心脏代谢疾病的风险。这些观察结果强调了表观遗传因素是将父母的饮食与其后代的程序性健康不良联系起来的一种潜在机制。虽然已经确定了父母一方单独饮食不平衡的受孕后后果，但关于父母双方饮食对后代健康的相互影响的信息很少，也没有关于干扰对单碳代谢影响的数据；我们已经证明，这是胚胎发育和后代健康的表观遗传调控的核心。假设：饮食中维生素B12和叶酸的缺乏已被证明会扰乱父母的单碳代谢，导致后代的表观遗传改变，从而扰乱他们的发育、健康和幸福。我们假设，如果父母双方都吃同样的次优、低B12/叶酸饮食（这在人类夫妇中很可能发生），这将比父母一方单独对后代的发育和福祉产生更大的影响。父母遗传的表观遗传修饰驱动基因表达、组织功能和后代生长的差异模式将成为这些影响的基础。目的：在一个因子安排的设计中，我们将通过在交配前7周给雄性和雌性小鼠喂食低B12/叶酸饮食或控制饮食来确定父母对后代健康的特定贡献，以确保配子发育和成熟的所有阶段都暴露在饮食中。然后将雄性和雌性结合进行交配，以确定：(1)父亲单独的低碳饮食的具体影响；（ii）母亲单独低碳饮食，（iii）父母联合低碳饮食或（iv）父母联合对照饮食。方法：在整个饲养期间，采集母系和父系血液样本，检测单碳代谢的代谢终点（采用LC-MS/MS (Antonysunil实验室，NTU)）。