Human Equivalent Dose Modeling for Omega-3 Fatty Acid Supplementation in C57BL/6J Mice

The rodent model is often used to study the impact of dietary n-3 fatty acids on a variety of biological endpoints, and the results of these studies have been used to explain anticipated effects of n-3 fatty acid intake in humans. However, supplemental levels of n-3 fatty acids that are commonly used in rodent studies do not represent reasonable human intake, by comparison. Currently there is no standard method for the addition of n-3 fatty acids to rodent diets. We tested a mathematical model for dosing supplemental levels of α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) to rodent diets on the basis of energy%. C57BI/6J mice were fed a background diet that modeled typical Western intake in both macronutrient and fatty acid composition. Three levels of ALA and EPA (0.3, 0.8, and 1.4 energy%) were supplemented to either a normal-ALA control diet (0.6 energy% ALA) or a high-ALA control diet (1.2 energy% ALA). Plasma and erythrocyte phospholipid fatty acid changes were determined and compared to archival human n-3 fatty acid supplementation studies reporting the same tissue endpoints. In mice, supplemental EPA had a greater effect than supplemental ALA on both plasma and erythrocyte phospholipid EPA. Docosahexaenoic acid (DHA) levels in mice were only minimally changed by either ALA or EPA supplementation. Use of the high- ALA control diet resulted in attenuated phospholipid fatty acid changes in both tissues compared to the normal-ALA control diet for both supplemented fatty acids. At each supplemented dose of ALA or EPA, changes in murine plasma or erythrocyte phospholipid EPA exceeded changes observed in the same human tissues by 2-4 fold when compared to equivalent human supplemental doses in energy%. Tissue changes observed using the high-ALA control diet better modeled the results observed in humans at the same supplemental energy% for both ALA and EPA in plasma and erythrocyte phospholipids. This is the first study to use pharmacodynamic modeling to compare the effect of supplemental n-3 doses on mouse and human endpoints. The addition of n-3 fatty acids to rodent diets on the basis of energy% represents a reasonable improvement to current dosing strategies. This data is useful both as a guideline for n-3 fatty acid dosing in rodent studies and as a reference point for future calculated refinements in dosing.