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

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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).