Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition

Abstract

The two-fold higher prevalence rate of major depression in females may involve vulnerability to omega-3 fatty acid deficiency secondary to a dysregulation in ovarian hormones. However, the role of ovarian hormones in the regulation of brain omega-3 fatty acid composition has not been directly evaluated. Here we determined erythrocyte and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition in intact male and female rats, and in chronically ovariectomized (OVX) rats with or without cyclic estradiol treatment (2 microg/4d). All groups were maintained on diets with or without the DHA precursor alpha-linolenic acid (ALA, 18:3n-3). We report that both male (-21%) and OVX (-19%) rats on ALA+ diet exhibited significantly lower erythrocyte DHA composition relative to female controls. Females on ALA+ diet exhibited lower DHA composition in the prefrontal cortex (PFC) relative males (-5%). OVX rats on ALA+ diet exhibited significantly lower DHA composition in the hippocampus (-6%), but not in the PFC, hypothalamus, or midbrain. Lower erythrocyte and hippocampus DHA composition in OVX rats was not prevented by estrogen replacement. All groups maintained on ALA- diet exhibited significantly lower erythrocyte and regional brain DHA composition relative to groups on ALA+ diet, and these reductions were greater in males but not in OVX rats. These preclinical data corroborate clinical evidence for gender differences in peripheral DHA composition (female>male), demonstrate gender differences in PFC DHA composition (male>female), and support a link between ovarian hormones and erythrocyte and region-specific brain DHA composition.

Fig. 1

Mean DHA composition in erythrocytes (A) and PFC (B) of male and female rats on ALA+ or ALA− diets (n=10–22/group). Note that male rats on ALA+ diet exhibit lower erythrocyte DHA composition relative to female rats, and (2) male rats on ALA− diet exhibit greater reductions in erythrocyte and PFC DHA composition relative to females. Values are group mean ± S.E.M. ** P≤0.01, ***P≤0.001 vs. females on the same diet, ^###P≤0.0001 vs. same gender on ALA+ diet.

Fig. 2

Mean DHA composition in erythrocytes (A) and PFC (B) of female rats (n=22) on ALA+ diet segregated according to their position in the ovarian cycle (M, metestrus [D1]; D, diestrus; E, estrus). Note that erythrocyte and PFC DHA composition do not differ significantly between ovarian phases. Values are group mean ± S.E.M.

Fig. 3

Mean DHA composition in erythrocytes of sham controls, OVX, and OVX+E rats on ALA+ or ALA− diets (n=6–14/group). Note that OVX rats on ALA+ or ALA− diet exhibit a significant reduction in erythrocyte DHA composition relative shams on the same diet, and cyclic estradiol treatment partially normalizes erythrocyte DHA composition in OVX rats on ALA− but not ALA+ diet. Values are group mean ± S.E.M. **P = 0.003 vs. shams on the same diet, ^###P≤0.0001 vs. same group on ALA+ diet,

Fig. 4

Mean DHA composition in the PFC (A), hippocampus (B), hypothalamus (C), and midbrain (D) of sham controls, OVX, and OVX+E rats on ALA+ or ALA− diets (n=6–7/group). Note that OVX rats on ALA+, but not ALA− diet, exhibit significantly lower hippocampus DHA composition relative to shams on the same diet. Values are group mean ± S.E.M. **P=0.006 vs. shams on ALA+ diet, ^###P≤0.0001 vs. same group on ALA+ diet.