Grant: Discovery Grants Program - Individual

OVERALL AIM OF THE PROGRAM: My NSERC-Discovery Grant program is to understand the mechanisms by which maternal dietary fats regulate offspring metabolism. The long-term goal is to better understand how fatty acids (FA) act as regulators of gene expression to affect metabolism, cell death and survival pathways, and neuronal or inflammatory processes. BACKGROUND: The omega (n)-3 polyunsaturated fatty acids (PUFA) are transported across the placenta for proper growth and development of the fetus. An optimal amount of n-3 PUFA is also essential for maintaining pregnancy. We have previously demonstrated that sustained exposure to maternal and post-weaning diets low in n-3 PUFA have adverse effects on offspring lipid levels, along with lower accretion of n-3 PUFA and a lower gene expression of neurotrophins in brain. However, whether the effects of maternal diets low in n-3 PUFA can be reversed by post-weaning diets high in n-3 PUFA is not known. We also observed a smaller litter size in mice fed a low n-3 PUFA diet. Literature reports inconsistent effects of n-3 PUFA on pregnancy outcome. It is thus important to establish the optimum amount of n-3 PUFA, to maintain maternal metabolism during pregnancy, for a favorable pregnancy outcome; and to investigate the mechanisms by which n-3 PUFA influences pregnancy outcome. The specific objectives in the short-term are: 1) To establish the amount of n-3 PUFA (and/or n-6:n-3 PUFA) for favorable pregnancy outcome, and to investigate the mechanisms by which n-3 PUFA maintain the in utero environment; 2) To investigate whether switching the offspring fed a low n-3 PUFA diet during gestation/lactation, to a post-weaning diet high in n-3 PUFA, will reverse the effects of maternal diets. EXPERIMENTAL DESIGN: Female C57BL/6 mice will be fed diets varying in the amount of n-3 PUFA (and/or n-6:n-3 PUFA) before mating, throughout gestation (Objective 1), and lactation/post-weaning (Objective 2). Maternal plasma and tissues will be collected at gestation day (GD) 6.5, 12.5 and 18.5. Implantation sites will be checked at GD 6.5; fetal numbers/weight will be recorded at GD 12.5 and 18.5. The regulation of maternal lipid metabolism will be studied at each GD. Maternal sex-steroids, cytokines, and gene expression of placental FA transporters will be measured at each GD. Incorporation of n-3 PUFA in fetal brain, and the gene expression of neurotrophins will be measured at GD 12.5 and 18.5. Lipidomics profile of maternal plasma and placenta, and of fetal brain, will identify novel lipids. The effects of switching the offspring to a diet high in n-3 PUFA, at weaning, or in adulthood, will be studied on offspring lipid metabolism, and the accretion of n-3 PUFA and neurotrophins gene expression in brain. IMPACT: The findings will advance our knowledge on the role of n-3 PUFA in pregnancy. Our findings will also help to design diets for animal breeding, or towards human health/pregnancy. Several HQP will be trained.