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

背景资料：人类流行病学数据和动物研究表明，怀孕期间父母饮食不佳会增加多代后代患心脏代谢疾病的风险。这些观察结果突出了表观遗传因素作为一种潜在的机制，将父母的饮食与其后代的程序性疾病联系起来。虽然已经建立了单独的父母一般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，也没有关于干扰对一碳代谢影响的数据;我们已经证明这对胚胎发育和后代健康的表观遗传调节至关重要。假设：维生素B12和叶酸的饮食缺乏已被证明会干扰父母的一碳代谢，导致后代的表观遗传修饰，从而干扰他们的发育，健康和福祉。我们假设，如果父母双方都食用同样的次优，低B12/叶酸饮食（这很可能发生在人类夫妇中），这将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：在一项析因安排的设计中，我们将通过在交配前7周喂食雄性和雌性小鼠低B12/叶酸饮食或对照饮食，以确保配子发育和成熟的所有阶段都暴露于饮食，来定义亲代特异性对后代健康的贡献。然后将雄性和雌性组合交配，以确定（i）单独的父本低一碳饮食;（ii）单独的母本低一碳饮食，（iii）组合的亲本低一碳饮食或（iv）组合的对照亲本饮食的具体影响。方法：在整个喂养期间，将采集母体和父体血液样本，并测定一碳代谢的代谢终点（通过LC-MS/MS（Antonysunil lab，NTU））。

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).