Applying compound specific isotope analysis (CSIA) to elucidate sex differences in docosahexaenoic acid (DHA) synthesis and metabolism

Background: Women consistently demonstrate higher DHA levels than men. The proposed mechanism for this is higher DHA synthesis rates from the nutritionally essential n-3 PUFA, ALA; however, this remains to be assessed.

Objectives: 1) Determine sex differences in mouse liver DHA synthesis and turnover rates to identify where in the n-3 PUFA synthesis pathway sex differences may occur and 2) develop a translational CSIA model for use in humans.

Methods: C57BL/6 mice were allocated to one of three 12-week dietary interventions: 1) 4-week low carbon-13 (δ¹³C)-ALA diet à 8-week high δ¹³C-ALA diet, 2) 4-week low δ¹³C-EPA diet à 8-week high δ¹³C-EPA diet or 3) 4-week low δ¹³C-DHA diet à 8-week high δ¹³C-DHA diet (n=4 per diet, per time point, per sex). On days 0, 1, 3, 7, 14, 28, 56 post-diet-switch blood was collected from the left ventricle, animals were perfused with cold saline and liver, heart, brain, adipose and whole bodies were collected to determine DHA synthesis and turnover rates.

Results: Hepatic DHA synthesis rates were not different between male and female mice. However, hepatic DPAn-3 synthesis rates from dietary EPA were higher in males compared to females. In the heart, DPAn-3 turnover from dietary ALA and EPA was higher in males compared to females in their respective dietary groups, while inversely, DHA turnover rates were higher in females than in males. Additionally, serum and liver DHA half-lives were statistically the same.

Significance: Females may have a compensatory increase in synthesis downstream of DPAn-3, encouraging further assessment of DHA synthesis from DPAn-3 and THA, the immediate precursor to DHA. Furthermore, matching serum and liver half-lives support translation of this model to determine sex-specific differences in DHA synthesis from dietary ALA in humans.