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

Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0516, United States.
Psychoneuroendocrinology (Impact Factor: 4.94). 12/2008; 34(4):532-9. DOI: 10.1016/j.psyneuen.2008.10.013
Source: PubMed


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.

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Available from: Ronald Jandacek, Jun 27, 2014
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    • "Male Wistar rats were first made n-3 FAD over two generations. Male rats were chosen to avoid potential confounding effects of estrogen that have been reported in previous studies of ID and n-3 FAD [51,52]. At a commercial animal breeder (RCC), female Wistar rats (PND 21) were fed an n-3 FAD diet (detailed below), and were mated at 11 weeks with 12-week-old male breeders of the same strain. "
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    ABSTRACT: Background We recently showed that a combined deficiency of iron (ID) and n-3 fatty acids (n-3 FAD) in rats disrupts brain monoamine metabolism and produces greater memory deficits than ID or n-3 FAD alone. Providing these double-deficient rats with either iron (Fe) or preformed docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) alone affected brain monoamine pathways differently from combined repletion and even exacerbated cognitive deficits associated with double-deficiency. Iron is a co-factor of the enzymes responsible for the conversion of alpha-linolenic acid (ALA) to EPA and DHA, thus, the provision of ALA with Fe might be more effective in restoring brain EPA and DHA and improving cognition in double-deficient rats than ALA alone. Methods In this study we examined whether providing double-deficient rats with ALA and Fe, alone or in combination, can correct deficits in monoamine metabolism and cognition associated with double-deficiency. Using a 2 × 2 design, male rats with concurrent ID and n-3 FAD were fed an Fe + ALA, Fe + n-3 FAD, ID + ALA, or ID + n-3 FAD diet for 5 weeks (postnatal day 56–91). Biochemical measures, and spatial working and reference memory (using the Morris water maze) were compared to age-matched controls. Results In the hippocampus, we found a significant Fe × ALA interaction on DHA: Compared to the group receiving ALA alone, DHA was significantly higher in the Fe + ALA group. In the brain, we found significant antagonistic Fe × ALA interactions on serotonin concentrations. Provision of ALA alone impaired working memory compared with age-matched controls, while in the reference memory task ALA provided with Fe significantly improved performance. Conclusion These results indicate that providing either iron or ALA alone to double-deficient rats affects serotonin pathways and cognitive performance differently from combined provision. This may be partly explained by the enhancing effect of Fe on the conversion of ALA to EPA and DHA.
    Lipids in Health and Disease 06/2014; 13(1):97. DOI:10.1186/1476-511X-13-97 · 2.22 Impact Factor
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    • "Preclinical evidence further suggests that chronic treatment with SGA medications increases rat erythrocyte and heart EPA + DHA composition by augmenting biosynthesis [36] [37]. Furthermore, preclinical and clinical evidence suggests that ovarian hormones augment LCn − 3 fatty acid biosynthesis and erythrocyte DHA composition [38] [39] [40] [41], and that erythrocyte [31] and postmortem brain [35] DHA deficits are more robust in male than female SZ patients. The primary objective of the present study was to compare erythrocyte EPA + DHA composition in adult medication-free male and female SZ patients and healthy controls. "
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    ABSTRACT: Deficiency in long-chain omega-3 (LCn - 3) fatty acids, eicosapentaenoic acid (EPA, 20:5n - 3) and docosahexaenoic acid (DHA, 22:6n - 3), has been implicated in the pathoetiology of cardiovascular disease, a primary cause of excess premature mortality in patients with schizophrenia (SZ). In the present study, we determined erythrocyte EPA + DHA levels in adult medication-free patients SZ (n = 20) and age-matched healthy controls (n = 24). Erythrocyte EPA + DHA composition exhibited by SZ patients (3.5%) was significantly lower than healthy controls (4.5%, -22%, P = 0.007). The majority of SZ patients (72%) exhibited EPA+DHA levels ≤4.0% compared with 37% of controls (Chi-square, P = 0.001). In contrast, the omega-6 fatty acid arachidonic acid (AA, 20:4n - 6) (+9%, P = 0.02) and the AA:EPA + DHA ratio (+28%, P = 0.0004) were significantly greater in SZ patients. Linoleic acid (18:2n - 6) was significantly lower (-12%, P = 0.009) and the erythrocyte 20:3/18:2 ratio (an index of delta6-desaturase activity) was significantly elevated in SZ patients. Compared with same-gender controls, EPA + DHA composition was significantly lower in male (-19%, P = 0.04) but not female (-13%, P = 0.33) SZ patients, whereas the 20:3/18:2 ratio was significantly elevated in both male (+22%, P = 0.008) and female (+22%, P = 0.04) SZ patients. These results suggest that the majority of SZ patients exhibit low LCn - 3 fatty acid levels which may place them at increased risk for cardiovascular morbidity and mortality.
    Cardiovascular Psychiatry and Neurology 02/2013; 2013:796462. DOI:10.1155/2013/796462
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    • "This finding is consistent with previous work showing a lack of sex difference in cerebral cortex phospholipid DHA levels (Extier et al. 2010). One study showed higher prefrontal cortex total lipid DHA levels in males (McNamara et al. 2009), suggesting that sex differences in brain DHA content are specific to the brain area investigated. Brain DHA levels are quite stable throughout the lifetime of rats after weaning, as DHA-free artificial rearing (Lim et al. 2005; Ward et al. 1996) or multigenerational dietary DHA deficiency (Bourre et al. 1984) is required to reduce rat brain DHA stores. "
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    ABSTRACT: Docosahexaenoic acid (DHA, 22:6n-3) is higher in the blood and tissues of females relative to males, but the underlying mechanism is not clear. The present study examined the expression of enzymes involved in the biosynthesis of DHA from short-chain n-3 polyunsaturated fatty acids in male and female rats (n = 6 for each sex). Rats were maintained on an AIN-93G diet and sacrificed at 14 weeks of age after an overnight fast. Plasma, erythrocytes, liver, heart, and brain were collected for fatty acid composition analysis and the determination of enzyme and transcription factor expression by RT-PCR and immunoblotting. Females had higher DHA concentrations in the total lipids of liver, plasma, erythrocyte, and heart (53%, 75%, 36%, and 25% higher, respectively, compared with males) with no sex differences in brain DHA concentrations. The mRNA content of Δ5-desaturase, Δ6-desaturase, and elongase 2 was 1.0-, 1.4-, and 1.1-fold higher, respectively, in the livers of female rats compared with males, with no differences in the hearts or brains. The protein content of Δ6-desaturase was also higher in females. Higher hepatic mRNA of sterol-regulatory element-binding protein 1-c and estrogen receptor α in the females suggests that lipogenic and estrogen signaling mechanisms are involved. The sex difference in DHA concentration is tissue specific and is associated with higher Δ6-desaturase expression in females relative to males, which appears to be limited to the liver.
    Applied Physiology Nutrition and Metabolism 10/2012; 37(6). DOI:10.1139/h2012-103 · 2.34 Impact Factor
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