Dietary Precursors Research Articles

Phosphodiesterase 2 and 5 inhibition attenuates the object memory deficit induced by acute tryptophan depletion

The underlying mechanism of short-term memory improvement after inhibition of specific phosphodiesterases (PDEs) is still poorly understood. The present study aimed to reveal the ability of PDE5 and PDE2 inhibitors, that increase cyclic guanosine monophosphate (cGMP) and both cyclic adenosine monophosphate (cAMP) and cGMP, respectively, to reverse an object recognition deficit induced by acute tryptophan depletion. Acute tryptophan depletion is a pharmacological challenge tool to lower central serotonin (5-hydroxytryptamine; 5-HT) levels by depleting the availability of its dietary precursor tryptophan. Short-term object memory was tested in male Wistar rats by exposing them to the object recognition task. First, the effects of acute tryptophan depletion upon object recognition 2 h after administration of the nutritional mixture were established. Subsequently, acute tryptophan depletion was combined with the PDE5 inhibitor vardenafil (1, 3 and 10 mg/kg) or with the PDE2 inhibitor BAY 60-7550 (0.3, 1 and 3 mg/kg), 30 min prior to testing. Acute tryptophan depletion significantly lowered plasma tryptophan levels and impaired object recognition performance. Vardenafil (3 and 10 mg/kg) and BAY 60-7550 (3 mg/kg) were able to attenuate the acute tryptophan depletion induced object recognition impairment. Thus, both PDE5 and PDE2 inhibition improved short-term object recognition performance after an acute tryptophan depletion induced deficit. The underlying mechanisms, however, remain poorly understood and further studies are needed to determine whether the present findings can be explained by a direct effect of enhanced cAMP and cGMP levels upon 5-HT activity, or even other neurotransmitter systems, and possibly an interaction with synthesis of nitric oxide or effects upon cerebral blood flow function.

Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers

Reduced brain serotonin function is acknowledged as a vulnerability factor for affective disturbances. Since the production of serotonin is limited by the availability of its plasma dietary amino acid precursor tryptophan (TRP), the beneficial effects of tryptophan-rich alpha-lactalbumin whey protein (ALAC) have recently been studied. The effects of ALAC remain rather modest, and alternative protein sources of tryptophan may be more effective. We tested whether hydrolyzed protein (HPROT) has greater effects on the plasma TRP/large neutral amino acids (LNAA) ratio and mood than intact ALAC protein in healthy volunteers. In a double-blind, randomized cross-over study, plasma amino acids and mood were repeatedly measured in 18 healthy subjects before and after intake of ALAC and HPROT as well as after placebo protein, pure tryptophan, and a tryptophan-containing synthetic peptide. Except for the placebo protein, all interventions contained 0.8 g TRP. Significantly faster and greater increases in plasma TRP/LNAA were found after HPROT than after ALAC. In addition, the effects of HPROT on plasma TRP/LNAA were comparable with the effects of the tryptophan-containing synthetic peptide and even exceeded the effect of pure tryptophan. Sixty minutes after intake, mood was improved only following intake of HPROT and pure tryptophan, whereas longer-lasting mood effects were only found after intake of HPROT. The use of a tryptophan-rich hydrolyzed protein source may be more adequate to increase brain tryptophan and 5-HT function compared with intact alpha-lactalbumin protein or pure tryptophan.

Mechanism(s) of long chain n-3 essential fatty acid production in two species of heterotrophic protists: Oxyrrhis marina and Gyrodinium dominans

As intermediaries, some heterotrophic protists can enhance the content of the long chain n-3 essential fatty acids (LCn-3EFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), of low food quality algae for subsequent use at higher trophic levels. However, the mechanisms that produce LCn-3EFAs are presently unknown, although LCn-3EFA production by heterotrophic protists at the phytoplankton–zooplankton interface may potentially affect the nutritional status of the pelagic system. We investigated whether the heterotrophic protists, Oxyrrhis marina and Gyrodinium dominans, produce LCn-3EFAs via elongation and desaturation of dietary LCn-3EFA precursors and/or synthesize LCn-3EFAs de novo by: (1) feeding the two heterotrophic protists with a prey deficient in n-3 fatty acids, (2) incubating them in medium containing 13C-labeled sodium acetate, and (3) feeding the two protists gelatin acacia microspheres (GAMs) containing a deuterium-labeled LCn-3EFA precursor, linolenic acid [18:3(n-3)-d4]. Both O. marina and G. dominans synthesized EPA and DHA when fed the n-3 fatty acid-deficient prey, Perkinsus marinus, a parasitic protozoan. O. marina, but not G. dominans utilized 13C-labeled acetate from the medium to produce uniformly labeled fatty acids, including DHA. Both heterotroph species consumed GAMs containing 18:3(n-3)-d4 and catabolized 18:3(n-3)-d4 to 16:3(n-3)-d4 and 14:3(n-3)-d4, while no 20 or 22 carbon metabolites of 18:3(n-3)-d4 were detected. These results suggest that O. marina and G. dominans do not elongate and desaturate dietary LCn-3EFA precursors to produce LCn-3EFAs, but rather they produce LCn-3EFAs de novo, possibly via a polyketide synthesis pathway.

Dietary Amino Acids and Brain Serotonin Function; Implications for Stress-Related Affective Changes

Stress-related mood deterioration and affective disorders, such as depression, are among the leading causes of disease burden throughout the world, and are associated with severe medical consequences and mortality. Research has shown the involvement of dysfunctional brain serotonin (5-HT) biochemistry as a vulnerable biological factor in the onset of mood disturbances. Since the production of brain serotonin is limited by the availability of its plasma dietary amino acid precursor tryptophan, different foods and dietary amino acids that influence tryptophan availability are thought to alter affective behavior by changing brain 5-HT synthesis. Most dietary manipulation studies, however, reveal only modest affective changes, and note that these particularly occur in stress-prone or affected (sub-clinical) subjects. The current paper briefly summarizes evidence for the involvement of diminished brain serotonin function in affective disorders, discusses how this can be assessed and influenced by dietary manipulation procedures, and also notes how beneficial effects of dietary brain serotonin manipulation on affective behavior may be mediated by stress-induced brain serotonin vulnerability.

Dietary eicosapentaenoic acid and docosahexaenoic acid equally incorporate as decosahexaenoic acid but differ in inflammatory effects

Objective The ω-3 polyunsaturated fatty acids are involved in the modulation of the immune response. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) produced from dietary precursors may not be sufficient to match nutritional requirements and thus should be included in our diet. In this sense, the administration of higher amounts of DHA than of EPA in infant formulations is recommended. The aims of this work were to demonstrate that dietary administration of EPA or DHA to mice allows reaching similar tissue DHA levels and to compare their anti-inflammatory effects and mechanisms of action. Methods Balb/c mice were fed diets enriched with EPA or DHA for 3 wk. Twelve hours before sacrifice, a contact dermatitis was induced in the ears of the animals. Tissue fatty acid contents were determined. Cytokine and immunoglobulin concentrations were measured by enzyme-linked immunosorbent assay, and ears were collected to analyze local inflammatory effects. Results The DHA concentrations attained in tissues were similar to the two diets, whereas the EPA concentration increased only when the diet was enriched with this polyunsaturated fatty acid. Although EPA and DHA reduced ear inflammation, EPA reduced neutrophil infiltration in the ears more efficiently. EPA was associated with a greater reduction in the systemic macrophage inflammatory response and T-helper type 2 response and with increased interleukin-10 production. Conclusion Similar levels of DHA in tissues are reached in mice fed an EPA- or a DHA-enriched diet. Dietary EPA and DHA show anti-inflammatory properties, but EPA appears to be more potent.

Lipid Synthesis in Lactation: Diet and the Fatty Acid Switch

The lipid component of milk provides the critical nutritional source for generating both energy and essential nutrients to the growth of the newborn. Three types of substrate are utilized to synthesize milk triacylglycerides (TAG): dietary fat, fatty acids mobilized from adipose tissue stores, and lipids synthesized de novo synthesis from glucose and other dietary precursors, a process often referred to as de novo lipogenesis. The utilization of these various sources for TAG synthesis by the mammary epithelial cells is influenced by both the stage of lactation and the diet. From studies of gene expression in FVB mice, we observed that genes for beta-oxidation of fatty acids are downregulated along with the expression of Acyl-CoA thioesterase 1 (ACOT1). As a control mechanism we propose that during pregnancy ACOT1 provides a supply of cytoplasmic free fatty acids which increase the activation of PPARgamma. Ligand-induced activation of the PPAR/RXR transcription factor complex by free fatty acids, upregulates expression of genes required for beta-oxidation of fatty acids. The fall in ACOTs at secretory activation may facilitate the switch to lipogenesis perhaps mediated by activation of the LXR/RXR transcription factor complex. The response to changes in the supply of dietary lipids, on the other hand, is likely to be mediated by SREBP1, possibly acting through modulation of Spot 14. Stability of SREBP1 may be enhanced by a significant increase in Akt at secretory activation. These regulatory pathways may be critical to the production of milk with a balanced TAG composition to support neonatal development of the newborn.

Effect of a Soy Protein-Based Diet on Ribonucleic Acid Metabolism in the Small Intestinal Mucosa of Goat Kids

This study was designed to investigate the effect of soy protein inclusion in milk replacer diets for goat kids on protein, RNA, and DNA contents in small intestinal mucosa, on the importance of RNA biosynthesis from dietary RNA precursors for mucosal RNA synthesis, and on the activities of enzymes involved in nucleotide degradation in small intestinal mucosa. Diets were based on cow's milk. In the control group, 35% of the milk protein was replaced by casein (CN) protein, and in the soy group (SPAA), the same amount of milk protein was replaced by soy protein supplemented with essential AA known to be at lower concentrations in soy than in CN (Thr, Val, Ile, Leu, His, Lys, Met). Diets were isonitrogenous and isoenergetic. At 47 d of age, goats were harvested and samples of proximal, middle, and distal jejunal mucosa were collected 5h after feeding 15N-labeled RNA from yeast (13 mg/kg of body weight). Growth and feed conversion did not differ between the control and SPAA kids. Mucosal protein concentrations were lower in the SPAA than the control kids. Concentrations of RNA and DNA did not differ between feeding groups, but in all kids mucosal RNA concentrations were higher in proximal than in middle and distal jejunum. Protein:RNA ratios were higher in the control than the SPAA kids and were lowest in proximal jejunum. Activities of alkaline phosphatase in enterocytes were higher in proximal than in middle and distal jejunum. Activities of mucosal xanthine oxidase were highest in distal jejunum and were higher in the SPAA than the control kids, especially in the middle and distal sites. The 15N-enrichment of mucosal RNA was higher in the control than the SPAA kids, especially in distal jejunum, and was lowest in distal jejunum. In contrast, 15N-enrichment of urea in plasma tended to be higher and Gly concentration in plasma was lower in the SPAA than the control kids. Data indicate that protein content and the protein:RNA ratio were lower in jejunal mucosa of goat kids fed milk replacer with partial replacement of CN protein by soy protein. These findings were accompanied by a lower level of reutilization of preformed dietary RNA precursors for RNA biosynthesis in jejunal mucosa and a higher activity of xanthine oxidase. Thus, feeding soy protein instead of CN protein reduced the incorporation of preformed dietary RNA precursors for RNA biosynthesis in the mucosa and activated key enzymes involved in nucleic acid breakdown.

Silencing of beta-carotene hydroxylase increases total carotenoid and beta-carotene levels in potato tubers

BackgroundBeta-carotene is the main dietary precursor of vitamin A. Potato tubers contain low levels of carotenoids, composed mainly of the xanthophylls lutein (in the beta-epsilon branch) and violaxanthin (in the beta-beta branch). None of these carotenoids have provitamin A activity. We have previously shown that tuber-specific silencing of the first step in the epsilon-beta branch, LCY-e, redirects metabolic flux towards beta-beta carotenoids, increases total carotenoids up to 2.5-fold and beta-carotene up to 14-fold.ResultsIn this work, we silenced the non-heme beta-carotene hydroxylases CHY1 and CHY2 in the tuber. Real Time RT-PCR measurements confirmed the tuber-specific silencing of both genes . CHY silenced tubers showed more dramatic changes in carotenoid content than LCY-e silenced tubers, with beta-carotene increasing up to 38-fold and total carotenoids up to 4.5-fold. These changes were accompanied by a decrease in the immediate product of beta-carotene hydroxylation, zeaxanthin, but not of the downstream xanthophylls, viola- and neoxanthin. Changes in endogenous gene expression were extensive and partially overlapping with those of LCY-e silenced tubers: CrtISO, LCY-b and ZEP were induced in both cases, indicating that they may respond to the balance between individual carotenoid species.ConclusionTogether with epsilon-cyclization of lycopene, beta-carotene hydroxylation is another regulatory step in potato tuber carotenogenesis. The data are consistent with a prevalent role of CHY2, which is highly expressed in tubers, in the control of this step. Combination of different engineering strategies holds good promise for the manipulation of tuber carotenoid content.

Plumage carotenoids of the Pin-tailed Manakin ( Ilicura militaris): Evidence for the endogenous production of rhodoxanthin from a colour variant

The Pin-tailed Manakin ( Ilicura militaris) is a small, sexually dimorphic, frugivorous suboscine songbird (Pipridae; Passeriformes; Aves) endemic to the Atlantic Forest of Brazil. A variant individual of this species was recently described in which the red patches that characterise the male's Definitive plumage were replaced by orange–yellow ones. We show here that the pigments in the feathers of the colour variant are common dietary carotenoids (zeaxanthin, β-cryptoxanthin), not carotenoids synthesised by birds, lending support to the suggestion that the individual is a colour mutant lacking the capability to transform yellow dietary pigments into the red pigments normally present in these feathers. By comparison, the yellow crown feathers of a close relative, the Golden-winged Manakin ( Masius chrysopterus), contained predominantly endogenously produced ε-caroten-3′-ones. Surprisingly, the normal-coloured feathers of the male Pin-tailed Manakin owe their red hue to rhodoxanthin, an unusual carotenoid more commonly found in plants, rather than 4-keto-carotenoids typically found in red plumages and found lacking in previously characterised bird colour variants. The implication is that birds, like the tilapia fish, may be able to synthesise this unusual pigment endogenously from dietary precursors. A newly described carotenoid, 6-hydroxy-ε,ε-carotene-3,3′-dione, here named piprixanthin, present in the red feathers of the Pin-tailed Manakin, provides a plausible intermediate between ε,ε-carotene-3,3′-dione (canary-xanthophyll B), a bright yellow pigment found in this and other songbirds, and rhodoxanthin. It is apparent that pigeons (Columbidae, Columbiformes) also have the capability to produce rhodoxanthin, and a structurally related pigment, endogenously. The ability to synthesise rhodoxanthin might have arisen at least twice in birds.

Docosahexaenoic acid, the aquatic diet, and hominin encephalization: Difficulties in establishing evolutionary links

Distinctive characteristics of modern humans, including language, tool manufacture and use, culture, and behavioral plasticity, are linked to changes in the organization and size of the brain during hominin evolution. As brain tissue is metabolically and nutritionally costly to develop and maintain, early hominin encephalization has been linked to a release of energetic and nutritional constraints. One such nutrient-based approach has focused on the n-3 long-chained polyunsaturated fatty acid docosahexaenoic acid (DHA), which is a primary constituent of membrane phospholipids within the synaptic networks of the brain essential for optimal cognitive functioning. As biosynthesis of DHA from n-3 dietary precursors (alpha-linolenic acid, LNA) is relatively inefficient, it has been suggested that preformed DHA must have been an integral dietary constituent during evolution of the genus Homo to facilitate the growth and development of an encephalizing brain. Furthermore, preformed DHA has only been identified to an appreciable extent within aquatic resources (marine and freshwater), leading to speculation that hominin encephalization is linked specifically to access and consumption of aquatic resources. The key premise of this perspective is that biosynthesis of DHA from LNA is not only inefficient but also insufficient for the growth and maturation demands of an encephalized brain. However, this assumption is not well-supported, and much evidence instead suggests that consumption of LNA, available in a wider variety of sources within a number of terrestrial ecosystems, is sufficient for normal brain development and maintenance in modern humans and presumably our ancestors.

The retina is more susceptible than the brain and the liver to the incorporation oftransisomers of DHA in rats consumingtransisomers of alpha-linolenic acid

Trans polyunsaturated fatty acids are formed during heat treatments of vegetable oils from polyunsaturated fatty acids containing cis double bonds. After dietary intake, they are distributed in the body and are incorporated into nervous tissues including the retina. Since nervous tissues are known to be rich in n-3 fatty acids such as docosahexaenoic acid (DHA), we studied the ability of the retina and the brain to incorporate trans isomers of DHA formed in vivo from the dietary precursor trans alpha-linolenic acid. Wistar rats were fed with trans isomers of alpha-linolenic acid for 21 months. A linear incorporation of trans DHA and a decrease in cis DHA was observed in the retina, whereas no major changes were observed in the brain. In parallel to the modifications in retinal cis and trans DHA levels, the retinal functionality evaluated by the electroretinogram showed defects in animals that consumed trans alpha-linolenic acid. These results suggest that the mechanisms leading to the incorporation of cis and trans fatty acids are quite different in the retina when compared to the brain and the liver, the retina being more susceptible to changes in the dietary lipid contribution.

Assessing Exposure to Lignans and Their Metabolites in Humans

Phytoestrogens occur naturally in plants and are structurally similar to mammalian estrogens. The lignans are a class of phytoestrogen and can be metabolized to the biologically active enterolignans, enterodiol, and enterolactone by a consortium of intestinal bacteria. Secoisolariciresinol diglucoside (SDG), a plant lignan, is metabolized to enterodiol and, subsequently, enterolactone. Matairesinol, another plant lignan, is metabolized to enterolactone. Other dietary enterolignan precursors include lariciresinol, pinoresinol, syringaresinol, arctigenin, and sesamin. Enterolignan exposure is determined in part by intake of these precursors, gut bacterial activity, and host conjugating enzyme activity. A single SDG dose results in enterolignan appearance in plasma 8-10 h later--a timeframe associated with colonic bacterial metabolism and absorption. Conjugation of enterolignans with sulfate and glucuronic acid occurs in the intestinal wall and liver, with the predominant conjugates being glucuronides. Controlled feeding studies have demonstrated dose-dependent urinary lignan excretion in response to flaxseed consumption (a source of SDG); however, even in the context of controlled studies, there is substantial interindividual variation in plasma concentrations and urinary excretion of enterolignans. The complex interaction between colonic environment and external and internal factors that modulate it likely contribute to this variation. Knowledge of this field, to date, indicates that understanding the sources of variation and measuring the relevant panel of compounds are important in order to use these measures effectively in evaluating the impact of lignans on human health.

1‐O‐alkyl‐2‐(ω‐oxo)acyl‐sn‐glycerols from shark oil and human milk fat are potential precursors of PAF mimics and GHB

This study examines the feasibility that peroxidation and lipolysis of 1-O-alkyl-2,3-diacyl-sn-glycerols (DAGE) found in shark liver oil and human milk fat constitutes a potential source of dietary precursors of platelet activating factor (PAF) mimics and of gamma-hydroxybutyrate (GHB). Purified DAGE were converted into 1-O-alkyl-2-acyl-sn-glycerols by pancreatic lipase, without isomerization, and transformed into 1-O-alkyl-2-oxoacyl-sn-glycerols by mild autooxidation. The various core aldehydes without derivatization, as well as the corresponding dinitrophenylhydrazones, were characterized by chromatographic retention time and diagnostic ions by online electrospray mass spectrometry. Core aldehydes of oxidized shark liver oil yielded 23 molecular species of 1-O-alkyl-sn-glycerols with short-chain sn-2 oxoacyl groups, ranging from 4 to 13 carbons, some unsaturated. Autooxidation of human milk fat yielded 1-O-octadecyl-2-(9-oxo)nonanoyl-sn-glycerol, as the major core aldehyde. Because diradylglycerols with short fatty chains are absorbed in the intestine and react with cytidine diphosphate-choline in the enterocytes, it is concluded that formation of such PAF mimics as 1-O-alkyl-2-(omega-oxo)acyl-sn-glycerophosphocholine from unsaturated dietary DAGE is a realistic possibility. Likewise, a C4 core alcohol produced by aldol-keto reduction of a C4 core aldehyde constitutes a dietary precursor of the neuromodulator and recreational drug GHB, which has not been previously pointed out.

Metabolic engineering of potato tuber carotenoids through tuber-specific silencing of lycopene epsilon cyclase

BackgroundPotato is a major staple food, and modification of its provitamin content is a possible means for alleviating nutritional deficiencies. beta-carotene is the main dietary precursor of vitamin A. Potato tubers contain low levels of carotenoids, composed mainly of the xanthophylls lutein, antheraxanthin, violaxanthin, and of xanthophyll esters. None of these carotenoids have provitamin A activity.ResultsWe silenced the first dedicated step in the beta-epsilon- branch of carotenoid biosynthesis, lycopene epsilon cyclase (LCY-e), by introducing, via Agrobacterium-mediated transformation, an antisense fragment of this gene under the control of the patatin promoter. Real Time measurements confirmed the tuber-specific silencing of Lcy-e. Antisense tubers showed significant increases in beta-beta-carotenoid levels, with beta-carotene showing the maximum increase (up to 14-fold). Total carotenoids increased up to 2.5-fold. These changes were not accompanied by a decrease in lutein, suggesting that LCY-e is not rate-limiting for lutein accumulation. Tuber-specific changes in expression of several genes in the pathway were observed.ConclusionThe data suggest that epsilon-cyclization of lycopene is a key regulatory step in potato tuber carotenogenesis. Upon tuber-specific silencing of the corresponding gene, beta-beta-carotenoid and total carotenoid levels are increased, and expression of several other genes in the pathway is modified.

Dr. Jiang Replies

Back to table of contents Previous article Next article Letters to the EditorFull AccessDr. Jiang RepliesWEI JIANG M.D.,WEI JIANG M.D.Search for more papers by this author,Published Online:1 Jun 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Thanks to Dr. Penland for bringing up these thought-provoking and challenging topics. I appreciate his contemplation and valiancy. The role of lipids in brain function is significant. Thirty years ago, lipids were described in a great textbook of biochemistry as being unlike nucleic acids and proteins—that they “do not have information-carrying function” (1) . With the series of convergent discoveries in the fields of neural development, synaptic physiology, and receptor pharmacology, the roles played by lipids and their receptors in brain function are being addressed in neuroscience. Lipids comprise 50%–60% of the dry weight of the adult brain, of which approximately 35% are in the form of long-chain polyunsaturated fatty acids. These polyunsaturated fatty acids are derived through biosynthesis from their respective dietary essential fatty acid precursors, linoleic acid and α-linolenic acid or directly from dietary sources such as eggs, fish, and meat or from single-cell oils. Dietary fat profoundly affects gene expression through binding directly with transcription factors or through eicosanoid regulation of intracellular signaling cascades, which results in alterations in metabolism, growth, and cell differentiation (2) . Chronic N -3 fatty acid deficiency has been found to reduce dopamine receptor binding and increase serotonin receptor density in the frontal cortex of both young and aged rats as well as to alter dopamine metabolism (3 – 5) . A formula low in linoleic acid and α-linolenic acid has been reported to result in low serotonin and dopamine levels in the frontal cortex of adult pigs (6) . The dynamic function of lipids, lipid signaling, was well described by Piomelli (7) as having four defining features: 1) the generation of informational diversity through permutation of simple structural units; 2) the “pervasive use of serial signaling”—that is, the application of a single biochemical pathway to multiple signaling needs; 3) the adoption of a signaling modality defined by the rapid on-demand response to primary signaling events, such as receptor activation; and 4) the localized nature of lipid-mediated signaling. Piomelli stated that in no other mammalian tissue do such features emerge more clearly than in the brain, where the roles of lipid messengers extend from the development of the neocortex to the processing of behavior. He further emphasized the diversity, the heterogeneity, and the complexity of the roles of lipids in the brain, as reflected by the discussion of the varieties of lipids classes “not only among different cell types, but also among different organelles of the same cell.” In fact, heterogeneities exist even within individual cell membranes between the inner and outer leaflet of the plasma membrane (8) and between “lipid rafts” and their surrounding membrane environment (9) . I have little doubt that disturbed lipids metabolization played a role in the psychiatric manifestation of the patient we presented (10) . However, because of minimal research on human behavior in rapid weight reduction or starvation, it remains speculative. I hope recent research in lipidomics that has been used to assess the brain function of lipids, with greater complexity, will bring definitive answers soon.Durham, N.C.Reprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.

CYP17 Genotype Modifies the Association between Lignan Supply and Premenopausal Breast Cancer Risk in Humans

Cytochrome P450c17alpha (CYP17) has been associated with alterations in steroid hormone levels and premenopausal breast cancer risk and could modify the association between phytoestrogen intake and breast cancer risk. We examined plasma concentrations of enterolactone and genistein, estimated dietary phytoestrogen intake, CYP17 5'-UTR MspA1 genetic polymorphism, and breast cancer risk in 267 premenopausal breast cancer patients and 573 age-matched population controls from Germany. Multivariate logistic regression was used to estimate breast cancer risk associated with quartiles of phytoestrogen intake by genotype and to investigate gene-nutrient interactions. Premenopausal breast cancer risk was not significantly associated with the CYP17 A2 genotype. We observed a significant modifying effect of CYP17 genotype on plasma enterolactone-associated breast cancer risk (P for interaction < 0.01). Plasma enterolactone was significantly inversely related to breast cancer risk only in A2A2 carriers, showing odds ratios and 95% CI of 0.02 (0.00-0.41) and 0.01 (0.00-0.21) for the third and fourth quartiles vs. the lowest quartile, respectively. This inverse association was also found for the calculated enterolignan production as well as matairesinol intake. Compared with A1A1 carriers with the lowest enterolactone supply, the risk reduction associated with a high enterolactone supply resulted in a comparably decreased breast cancer risk for all genotypes. For genistein, no clear indication for a differential effect by CYP17 genotype was obtained. Our results suggest that CYP17 genotype modifies the protective effect of lignans on premenopausal breast cancer risk. Women homozygous for A2 allele benefit most from high plasma enterolactone concentrations and a high consumption of dietary precursors.

Once and again: Retinoic acid signaling in the developing and regenerating olfactory pathway

Retinoic acid (RA), a member of the steroid/thyroid superfamily of signaling molecules, is an essential regulator of morphogenesis, differentiation, and regeneration in the mammalian olfactory pathway. RA-mediated teratogenesis dramatically alters olfactory pathway development, presumably by disrupting retinoid-mediated inductive signaling that influences initial olfactory epithelium (OE) and bulb (OB) morphogenesis. Subsequently, RA modulates the genesis, growth, or stability of subsets of OE cells and OB interneurons. RA receptors, cofactors, and synthetic enzymes are expressed in the OE, OB, and anterior subventricular zone (SVZ), the site of neural precursors that generate new OB interneurons throughout adulthood. Their expression apparently accommodates RA signaling in OE cells, OB interneurons, and slowly dividing SVZ neural precursors. Deficiency of vitamin A, the dietary metabolic RA precursor, leads to cytological changes in the OE, as well as olfactory sensory deficits. Vitamin A therapy in animals with olfactory system damage can accelerate functional recovery. RA-related pathology as well as its potential therapeutic activity may reflect endogenous retinoid regulation of neuronal differentiation, stability, or regeneration in the olfactory pathway from embryogenesis through adulthood. These influences may be in register with retinoid effects on immune responses, metabolism, and modulation of food intake.

Serum Enterolactone Concentration and the Risk of Coronary Heart Disease in a Case-Cohort Study of Finnish Male Smokers

The lignan enterolactone produced by the intestinal microflora from dietary precursors has been hypothesized to protect against coronary heart disease. The present study examined the association between serum enterolactone concentration and the risk of coronary heart disease. A prospective case-cohort study was conducted among male smokers randomized to receive a placebo supplement in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1986-1999). Serum enterolactone concentrations were measured by the gas chromatography-mass spectrometry method in serum collected at trial baseline from 340 men diagnosed with nonfatal myocardial infarction (n = 205) or coronary death (n = 135) during follow-up and from the randomly selected subcohort of 420 subjects. The classic risk factors-adjusted rate ratios for all coronary heart disease events in increasing quintiles of enterolactone were 1.00 (referent), 0.85 (95% confidence interval (CI): 0.51, 1.43), 0.59 (95% CI: 0.35, 1.00), 0.69 (95% CI: 0.40, 1.16), and 0.63 (95% CI: 0.33, 1.11), and the p(trend) was 0.07. For the highest versus the lowest quintile of enterolactone, the rate ratios for nonfatal myocardial infarction and coronary death were 0.67 (95% CI: 0.37, 1.23; p(trend) = 0.10) and 0.57 (95% CI: 0.26, 1.25; p(trend) = 0.18), respectively. In conclusion, only weak support for the association between serum enterolactone concentration and coronary heart disease was found.

Reduced Brain DHA Content After a Single Reproductive Cycle in Female Rats Fed a Diet Deficient in N-3 Polyunsaturated Fatty Acids

Low levels of n-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA, 22:6n3), are implicated in postpartum depression. The effects of pregnancy and lactation on brain phospholipid fatty acid content were determined in female rats fed diets containing sufficient (control) or negligible (deficient) alpha-linolenic acid (18:3n-3), the dietary precursor of DHA, beginning at conception. Female virgins, fed the diets for 6 weeks, served as control animals. Whole brain total phospholipid composition was determined at weaning by GC. Brain DHA content of postpartum dams fed the deficient diet was decreased by 21% compared with age-matched virgin control animals, with a reciprocal increase in docosapentaenoic acid (22:5n6) to 243%. Under dietary conditions supplying inadequate n-3 PUFAs, maternal brain DHA content can be reduced after a single reproductive cycle. This depletion may affect neuronal function and thus the sensitivity of the postpartum organism to stress.

Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children

Persistent trimethylaminuria in children is caused by autosomal recessively inherited impairment of hepatic trimethylamine (TMA) oxidation due to deficiency of flavin monooxygenase 3 (FMO3) secondary to mutations in the FMO3 gene. Trimethylaminuria or 'fish odour syndrome' is due to excessive excretion into body fluids and breath of TMA derived from the enterobacterial metabolism of dietary precursors. The disorder is present from birth but becomes apparent as foods containing high amounts of choline or of trimethylamine N-oxide (TMAO) from marine (sea or saltwater) fish are introduced into the diet. In our experience, trimethylaminuria (FMO3 deficiency) in children is rare. We have compared the dynamics and diagnostic efficacy of choline loading with marine fish meals in six children with trimethylaminuria. Loading with a marine fish meal provides a simple and acceptable method for confirmation of diagnosis of suspected trimethylaminuria in children, with the effects being cleared more quickly than with a choline load test. However, oral loading with choline bitartrate allows estimation of residual oxidative capacity in vivo and is a useful adjunct to molecular studies. Patients homozygous for the 'common' P153L mutation in the FMO3 gene showed virtual complete lack of residual TMA N-oxidative capacity, consistent with a nonfunctional or absent FMO3 enzyme, whereas a patient with the M82T mutation showed some residual oxidative capacity. A patient compound heterozygous for two novel mutations, G193E and R483T, showed considerable residual N-oxidative capacity. A further patient, heterozygous for two novel sequence variations in the FMO3 gene, consistently showed malodour and elevated urinary TMA/TMAO ratios under basal conditions but a negative response to both choline and marine fish meal loading. Comparison of the effects of administration of antibiotics (metronidazole, amoxicillin, neomycin) on gut bacterial production of trimethylamine from choline showed they all reduced TMA production to a limited extent, with neomycin being most effective. 'Best-practice' diagnostic and treatment guidelines are summarized.