Characterization of the effects of sex, pregnancy, and 17β-estradiol on docosahexaenoic acid biosynthesis

Abstract

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) required for fetal neurodevelopment. Increased DHA levels are associated with 17β-estradiol levels, as DHA is higher in women relative to men and in pregnant relative to non-pregnant women, suggesting a maternal adaptation to supply DHA to the fetus. DHA can be synthesized in the body from shorter n-3 PUFA through sequential elongation-desaturation, with Δ6-desaturase being the rate-limiting enzyme. The goal of the present thesis was to characterize the mechanism underlying higher DHA in situations of altered 17β-estradiol status by examining the expression of DHA synthesis enzymes in rodent models. Fatty acid composition of several lipid classes was measured by gas chromatography and enzyme expression was measured by RT-qPCR and immunoblotting. Hepatic Δ6-desaturase and phospholipid DHA was higher in female relative to male, and in pregnant relative to non-pregnant rats. Similarly, 17β-estradiol supplementation of ovariectomized rats resulted in increased hepatic Δ6-desaturase expression and DHA content, while ovariectomy itself had no effects on DHA levels despite controlling for hyperphagia. Mice deficient in the DNA binding activity of estrogen receptor α (ERα) had no differences in hepatic Δ6-desaturase or DHA levels. These results suggest that 17β-estradiol mediates the higher DHA levels in females and during pregnancy through increasing hepatic Δ6-desaturase expression, although the effects of removing 17β-estradiol signalling through ovariectomy or ERα disruption are less clear. This work helps to explain findings of altered DHA status in response to changes in 17β-estradiol concentrations, possibly resulting in more appropriately tailored dietary DHA recommendations. Also, increased understanding of the regulation of DHA synthesis may improve DHA yields in agri/aquaculture and enable increased content of DHA in the food supply.