Elevated production of docosahexaenoic acid in females: potential molecular mechanisms.

Observational evidence suggests that in populations consuming low levels of n-3 highly unsaturated fatty acids, women have higher blood levels of docosahexaenoic acid (DHA; 22:3n-6) as compared with men. Increased conversion of alpha-linolenic acid (ALA; 18:3n-3) to DHA by females has been confirmed in fatty acid stable isotope studies. This difference in conversion appears to be associated with estrogen and some evidence indicates that the expression of enzymes involved in synthesis of DHA from ALA, including desaturases and elongases, is elevated in females. An estrogen-associated effect may be mediated by peroxisome proliferator activated receptor-alpha (PPARalpha), as activation of this nuclear receptor increases the expression of these enzymes. However, because estrogens are weak ligands for PPARalpha, estrogen-mediated increases in PPARalpha activity likely occur through an indirect mechanism involving membrane-bound estrogen receptors and estrogen-sensitive G-proteins. The protein kinases activated by these receptors phosphorylate and increase the activity of PPARalpha, as well as phospholipase A(2) and cyclooxygenase 2 that increase the intracellular concentration of PPARalpha ligands. This review will outline current knowledge regarding elevated DHA production in females, as well as highlight interactions between estrogen signaling and PPARalpha activity that may mediate this effect.

Docosahexaenoic acid supplementation fully restores fertility and spermatogenesis in male delta-6 desaturase-null mice.

Delta-6 desaturase-null mice ((-/-)) are unable to synthesize highly unsaturated fatty acids (HUFAs): arachidonic acid (AA), docosahexaenoic acid (DHA), and n6-docosapentaenoic acid (DPAn6). The (-/-) males exhibit infertility and arrest of spermatogenesis at late spermiogenesis. To determine which HUFA is essential for spermiogenesis, a diet supplemented with either 0.2% (w/w) AA or DHA was fed to wild-type ((+/+)) and (-/-) males at weaning until 16 weeks of age (n = 3-5). A breeding success rate of DHA-supplemented (-/-) was comparable to (+/+). DHA-fed (-/-) showed normal sperm counts and spermiogenesis. Dietary AA was less effective in restoring fertility, sperm count, and spermiogenesis than DHA. Testis fatty acid analysis showed restored DHA in DHA-fed (-/-), but DPAn6 remained depleted. In AA-fed (-/-), AA was restored at the (+/+) level, and 22:4n6, an AA elongated product, accumulated in testis. Cholesta-3,5-diene was present in testis of (+/+) and DHA-fed (-/-), whereas it diminished in (-/-) and AA-fed (-/-), suggesting impaired sterol metabolism in these groups. Expression of spermiogenesis marker genes was largely normal in all groups. In conclusion, DHA was capable of restoring all observed impairment in male reproduction, whereas 22:4n6 formed from dietary AA may act as an inferior substitute for DHA.

Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration.

Delta-6 desaturase (D6D) catalyzes the first step in the synthesis of highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPAn-6), and docosahexaenoic (DHA) acids, as well as the last desaturation of DPAn-6 and DHA. We created D6D-null mice (-/-), which enabled us to study HUFA deficiency without depleting their precursors. In -/-, no in vivo AA synthesis was detected after administration of [U-(13)C]linoleic acid (LA), indicating absence of D6D isozyme. Unexpectedly, all of the -/- developed ulcerative dermatitis when fed a purified diet lacking D6D products but containing ample LA. The -/- also exhibited splenomegaly and ulceration in duodenum and ileocecal junction. Male -/- lacked normal spermatozoa with a severe impairment of spermiogenesis. Tissue HUFAs in -/- declined differentially: liver AA and DHA by 95%, and a smaller decrease in brain and testes. Dietary AA completely prevented dermatitis and intestinal ulcers in -/-. DPAn-6 was absent in -/- brain under AA supplementation, indicating absence of D6D isozyme for DPAn-6 synthesis from AA. This study demonstrated a distinct advantage of the D6D-null mice (-/-) to elucidate (1) AA function without complication of LA deprivation and (2) DHA function in the nervous system without AA depletion or DPAn-6 replacement seen in traditional models.

Serum testosterone is reduced following short-term phytofluene, lycopene, or tomato powder consumption in F344 rats.

Elevated serum androgens are associated with increased prostate cancer risk. Tomato consumption is also associated with reduced prostate cancer incidence, and the primary tomato carotenoid, lycopene, may modulate androgen activation in the prostate, yet little is known about other tomato carotenoids. To evaluate interrelations between phytofluene, lycopene, or tomato powder consumption and androgen status, 8-wk-old male F344 rats (fed a control AIN 93G diet) were castrated or sham-operated and subsequently provided with daily oral supplementation of phytofluene or lycopene ( approximately 0.7 mg/d) or fed a 10% tomato powder supplemented diet (AIN 93G) for 4 d. Sham-operated rats provided with either phytofluene, lycopene, or tomato powder had approximately 40-50% lower serum testosterone concentrations than the sham-operated, control-fed group. Tissue and serum phytofluene and lycopene concentrations were greater in castrated rats than in sham-operated rats, which may have been due in part to a decrease of hepatic CYP 3A1 mRNA expression and benzyloxyresorufin-O-dealkylase activity. Some changes in prostatic and testicular steroidogenic enzyme mRNA expression were found; in particular, prostate 17 beta-hydroxysteroid dehydrogenase 4 mRNA expression in castrated rats fed lycopene or tomato powder was 1.7-fold that of the sham-operated, control-fed group. Modest changes in mRNA expression of steroidogenic enzymes with short-term carotenoid intake may alter the flux of androgen synthesis to less potent compounds. Overall, results illustrate that short-term intake of tomato carotenoids significantly alters androgen status, which may partially be a mechanism by which tomato intake reduces prostate cancer risk.