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

背景：人类流行病学数据和动物研究表明，怀孕前后父母饮食不良会增加后代在多代人中患心脏代谢性疾病的风险。这些观察结果突出表明，表观遗传因素是将父母的饮食与其后代的程序性不良健康联系起来的一种潜在机制。虽然父母中任何一方单独饮食失衡的受孕后后果已经确定，但关于父母双方饮食对后代健康的交互影响的信息很少，也没有关于干扰一碳代谢的影响的数据；我们已经证明，这是胚胎发育和后代健康的表观遗传调节的核心。假设：维生素B12和叶酸的饮食不足已被证明扰乱父母的一碳代谢，导致后代的表观遗传改变，从而扰乱他们的发育、健康和福祉。我们假设，如果父母双方都摄入同样的次优、低B12/叶酸饮食(这种情况很可能发生在人类夫妇中)，这对后代发育和幸福的影响将比父母中的任何一方单独摄入更大。父母遗传的表观遗传修饰驱动了基因表达、组织功能和后代生长的不同模式，这将是这些影响的基础。目的：在析因设计中，我们将通过给雄性和雌性小鼠喂食低B12/叶酸饲料或对照饲料，在交配前7周，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这种饲料中。然后，雄性和雌性将结合在一起进行交配，以确定(I)父亲单独的低碳饮食；(Ii)母亲单独的低碳饮食，(Iii)父母低碳饮食的组合，或(Iv)组合对照父母饮食的具体影响。方法：在整个喂养期间，采集母亲和父亲的血液样本，并通过LC-MS/MS(Antonysunil Lab，NTU)分析一碳代谢的代谢终点。

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).