Flore Marchaland
Université de Bordeaux, Bordeaux INP, NutriNeuro, INRAE UMR 1286, Bordeaux, France
Title
Genetic maintenance of n-3 PUFA levels in offspring prevents the deleterious effects of maternal dietary n-3 PUFA deficiency
Abstract
N-3 and n-6 polyunsaturated fatty acids (PUFA) are essential fatty acids whose precursor forms are provided by plant foods. Once consumed, they are metabolized into long chain PUFA, notably docosahexaenoic acid (DHA, n-3) and arachidonic acid (ARA, n-6), which are the most abundant PUFA in the brain, esterified into neuronal and glial cell phospholipids. During perinatal period, they are transferred through placenta during gestation and milk during lactation. Thus, n-3 and n-6 PUFA levels accreted in the developing brain are highly reliant on maternal PUFA dietary intake. As a result, maternal dietary n-3 PUFA deficiency reduces n-3 PUFA and increases n-6 PUFA accretion in offspring's brain. We previously found that this imbalance between n-3 and n-6 PUFA leads to long-lasting alterations of spatial memory, morphological and functional parameters of hippocampal neurons, and hippocampal-cortical network connections in male offspring. These experimental findings are corroborated by clinical observations reporting a positive correlation between maternal n-3 PUFA status and children's cognitive performance. However, mechanisms by which n-3 PUFA impact brain development and cognitive trajectory, considering sex, remain poorly understood. Thus, by combining nutritional and genetic approaches, we developed a model allowing the maintenance of n-3 PUFA levels in offspring developing in a n-3 PUFA-deficient maternal environment, thanks to the fat-1 gene. This gene, not present in mammals, comes from C. elegans and converts n-6 into n-3 PUFA. We mated FAT-1 homozygous fathers with wild-type (WT) mothers to generate FAT-1 heterozygous offspring developing in a WT mother. Our findings show that perinatal exposure of these WT mothers to a n-3 PUFA-deficient diet decreases n-3 PUFA levels while increases n-6 PUFA levels in the brain of their WT pups, not their FAT-1 pups, who maintain n-3 PUFA levels similar to those of WT offspring from WT mothers fed a diet balanced in n-6/n-3 PUFA. This imbalanced PUFA ratio also impact cerebral levels of their bioactive derivatives, oxylipins, whose analysis reveals different profiles depending on the genotype and sex of the offspring. Moreover, at weaning, n-3 PUFA-deficient WT offspring display spatial memory impairment, in contrast to n-3 PUFA-deficient FAT-1 or n-3 PUFA-sufficient WT offspring. In addition, hippocampal pyramidal neurons display higher density of mature dendritic spine in n-3 PUFA-deficient FAT-1 compared to WT offspring. Finally, transcriptomic analysis of the hippocampus and cortex of the offspring reveals a significant down-regulation of mitochondrial metabolic pathways in n-3 PUFA-deficient FAT-1 compared to WT offspring. Overall, our results suggest that perinatal maintenance of n-3 PUFA levels mitigates alterations induced by maternal n-3 PUFA deficiency on neurodevelopment, in both male and female offspring, potentially explained by mitochondrial metabolism involvement.
Flore Marchaland1, Juliette Dupont Viratelle1, Flavie Crespo1, Stéphane Grégoire2,3, Heena-Vanmalibhain Brown1, Moïra Rossitto1, Jing Xuan Kang4, Niyazi Acar2,3, Charlotte Madore-Delpech1, Jean-Christophe Delpech1, Sophie Layé1
1Univ. Bordeaux, Bordeaux INP, NutriNeuro, INRAE UMR 1286, Bordeaux, France.
2Univ. Bourgogne, CNRS UMR 6265, Centre des Sciences du Goût et de l’Alimentation, Dijon, France.
3Univ. Bourgogne, INRAE UMR 1324, Centre des Sciences du Goût et de l’Alimentation, Dijon, France.
4Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA