The effects of sex and genetics on omega-3 polyunsaturated fatty acid metabolism

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Eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are omega-3 (n-3) polyunsaturated fatty acids (PUFA) that are high in fish and seafood, the accumulation of which regulates heart and brain function, and fetal/infant growth. However, EPA and DHA in the diets of Canadians is low and we often rely on their synthesis from the nutritionally essential alpha-linolenic acid (ALA, 18:3n-3). Although rates of DHA synthesis from ALA are thought to be low, I have published evidence that may refute this. Methods to assess DHA synthesis rates independent of turnover (i.e. its metabolic consumption to downstream products) are limited. Furthermore, previous animal models of DHA synthesis are not readily translated to humans due to high cost and invasiveness. Females, and in particular pregnant females, have higher DHA levels than males, and this has implications for optimal cardiac/neurological processes and fetal/infant development. Although these sex and pregnancy differences are often attributed to differences in the rates of DHA synthesis, the mechanistic evidence for this is limited as slower turnover of DHA may also explain higher DHA levels. Previously, I have demonstrated that females fed EPA and who had a genetic mutation for an enzyme (elongase 2) involved in the synthesis of DHA, increased DHA levels more than males. However, this and other studies have not been able to properly differentiate between sex differences in DHA synthesis or turnover. Consequently, the long-term objectives of my research program are 1) to develop a novel translational method for the characterization of DHA synthesis and turnover rates, and 2) investigate and understand the mechanisms related to the sex differences in DHA status. I will work towards these long-term goals by focusing on 3 major short-term objectives in the area of sex, pregnancy, genetics and n-3 PUFA metabolism:      1)elucidate differences in DHA synthesis and turnover rates between males and females      2)determine the role of estrogen and elongase 2 on sex differences in DHA metabolism      3)identify the mechanism of increased DHA levels during pregnancy and lactation I will address these goals by performing dietary experiments with mice (female vs. male and pregnancy), estrogen treatments, liver-specific elongase 2 knockout mice and fatty acid analyses for n-3 PUFA levels and carbon-13 abundance. This research will train MSc and BSc students while providing them with valuable research experience and scientific knowledge in the fields of nutrition, metabolism and biochemistry that can be used in a variety of other careers. The results of my research program will provide impactful new insights into the mechanisms explaining sex and pregnancy differences in DHA and n-3 PUFA levels. Understanding the mechanisms to explain higher DHA levels in females will help to provide targeted advice to individuals for improved heart and brain function, and fetal/infant development.