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Biomedical subjects

Steven H Zeisel

Publications and source records attributed to Steven H Zeisel.

At least 19 recordsLinked to original sources
PubMed2006

Dietary isoflavones differentially induce gene expression changes in lymphocytes from postmenopausal women who form equol as compared with those who do not.

Human and animal studies suggest that dietary soy isoflavones reduce cancer risk, ameliorate postmenopausal syndrome and decrease bone resorption in postmenopausal women. The capacity to form the metabolite equol from daidzein is suggested as an important modulator of response to isoflavones; this capacity depends on gut colonization with appropriate bacteria. We administered a dietary supplement containing high-dose purified soy isoflavones (genistein, 558 mg/day; daidzein, 296 mg/day; and glycitein, 44 mg/day) to 30 postmenopausal women for 84 days and collected peripheral lymphocytes at timed intervals. Using microarray analysis, we determined whether changes in gene expression associated with this treatment support existing hypotheses as to isoflavones' mechanisms of action. Expression of a large number of genes was altered by isoflavone treatment, including induction of genes associated with cyclic adenosine 3',5'-monophosphate (cAMP) signaling and cell differentiation and decreased expression of genes associated with cyclin-dependent kinase activity and cell division. We report that isoflavone treatment in subjects who have the capacity to produce equol differentially affects gene expression as compared with nonproducers, supporting the plausibility of the importance of equol production. In general, isoflavones had a stronger effect on some putative estrogen-responsive genes in equol producers than in nonproducers. Our study suggests that, in humans, isoflavone changes are related to increased cell differentiation, increased cAMP signaling and G-protein-coupled protein metabolism and increased steroid hormone receptor activity and have some estrogen agonist effects; equol-production status is likely to be an important modulator of responses to isoflavones.

Administration, Oral↗
PubMed2006

Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study.

BACKGROUND: Epidemiologic studies of choline and betaine intakes have been sparse because a food-composition database was not available until recently. The physiologic relevance of a variation in dietary choline and betaine in the general population and the validity of intake assessed by food-frequency questionnaire (FFQ) have not been evaluated. OBJECTIVE: This study was conducted to examine the physiologic relevance and validity of choline and betaine intakes measured by an FFQ. DESIGN: We examined the relations between choline and betaine intakes measured by FFQ and plasma total homocysteine (tHcy) concentrations in 1960 participants from the Framingham Offspring Study. RESULTS: Higher intakes of dietary choline and betaine were related to lower tHcy concentrations independent of other determinants, including folate and other B vitamins. For the lowest and highest quintiles of dietary choline plus betaine, the multivariate geometric means for tHcy were 10.9 and 9.9 mumol/L (P for trend < 0.0001). The inverse association was manifested primarily in participants with low folate intakes (P for interaction < 0.0001). Among participants with folate intakes < or =250 microg/d, the geometric mean tHcy concentrations in the lowest and highest quintiles of choline plus betaine intakes were 12.4 and 10.2 micromol/L (P for trend < 0.0001). Except for choline from phosphatidylcholine, individual forms of choline were inversely associated with tHcy concentrations. CONCLUSIONS: Our findings provide support for a physiologically important variation in choline and betaine intakes in the general population and for the validity of intake measured by FFQ.

Adult↗
PubMed2006

Status of nutrition education in medical schools.

BACKGROUND: Numerous entreaties have been made over the past 2 decades to improve the nutrition knowledge and skills of medical students and physicians. However, most graduating medical students continue to rate their nutrition preparation as inadequate. OBJECTIVE: The objective was to determine the amount and type of nutrition instruction at US medical schools, especially including the instruction that occurs outside designated nutrition courses. DESIGN: A 12-item survey asked nutrition educators to characterize nutrition instruction at their medical schools (required, optional, or not offered) and to quantify nutrition contact hours occurring both inside and outside designated nutrition courses. During 2004, we surveyed all 126 US medical schools accredited at that time. RESULTS: A total of 106 surveys were returned for a response rate of 84%. Ninety-nine of the 106 schools responding required some form of nutrition education; however, only 32 schools (30%) required a separate nutrition course. On average, students received 23.9 contact hours of nutrition instruction during medical school (range: 2-70 h). Only 40 schools required the minimum 25 h recommended by the National Academy of Sciences. Most instructors (88%) expressed the need for additional nutrition instruction at their institutions. CONCLUSION: With the move to a more integrated curriculum and problem-based learning at many medical schools, a substantial portion of the total nutrition instruction is occurring outside courses specifically dedicated to nutrition. The amount of nutrition education in medical schools remains inadequate.

Clinical Competence↗
PubMed2006

The evolution of Nutrition in Medicine, a computer-assisted nutrition curriculum.

The primary mission of the Nutrition in Medicine (NIM) project is to provide tools to facilitate the nutrition training of undergraduate medical students. NIM has developed and distributed a CD-ROM-based nutrition curriculum to medical schools since 1995. However, the medical school environment is changing rapidly; there is pressure to do more in less time, and many schools are emphasizing independent and integrated learning. The need for a nutrition curriculum that is more flexible and more accessible has driven the evolution of the NIM curriculum from CD-ROM-based delivery into a more modular curriculum with Web delivery. Such changes facilitate access and eliminate the need for installation of CD-ROMs and the associated technical support issues. In addition, the instructional units are smaller and more modular. Eventually, the authoring system will allow instructors to put together a course to meet their specific instructional needs. Our future plans also include custom-tailoring that will allow students to opt out of learning material on the basis of pretest scores if they are already proficient in the content. In this update, we provide a detailed description of the new system and the rationale for the modifications we made. Furthermore, we describe how each change addresses barriers to nutrition education as identified from our surveys and others and from direct user feedback. These innovative strategies should allow a better fit of NIM within diverse medical school environments and help to promote incorporation of the curriculum into more medical schools.

Computer-Assisted Instruction↗
PubMed2006

Choline deficiency increases lymphocyte apoptosis and DNA damage in humans.

BACKGROUND: Whereas deficiency of the essential nutrient choline is associated with DNA damage and apoptosis in cell and rodent models, it has not been shown in humans. OBJECTIVE: The objective was to ascertain whether lymphocytes from choline-deficient humans had greater DNA damage and apoptosis than did those from choline-sufficient humans. DESIGN: Fifty-one men and women aged 18-70 y were fed a diet containing the recommended adequate intake of choline (control) for 10 d. They then were fed a choline-deficient diet for up to 42 d before repletion with 138-550 mg choline/d. Blood was collected at the end of each phase, and peripheral lymphocytes were isolated. DNA damage and apoptosis were then assessed by activation of caspase-3, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and single-cell gel electrophoresis (COMET) assays. RESULTS: All subjects fed the choline-deficient diet had lymphocyte DNA damage, as assessed by COMET assay, twice that found when they were fed the control diet. The subjects who developed organ dysfunction (liver or muscle) when fed the choline-deficient diet had significantly more apoptotic lymphocytes, as assessed by the activated caspase-3 assay, than when fed the control diet. CONCLUSIONS: A choline-deficient diet increased DNA damage in humans. Subjects in whom these diets induced liver or muscle dysfunction also had higher rates of apoptosis in their peripheral lymphocytes than did subjects who did not develop organ dysfunction. Assessment of DNA damage and apoptosis in lymphocytes appears to be a clinically useful measure in humans (such as those receiving parenteral nutrition) in whom choline deficiency is suspected.

Adolescent↗
PubMed2006

Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains.

The availability of choline during critical periods of fetal development alters hippocampal development and affects memory function throughout life. Choline deficiency during fetal development reduces proliferation and migration of neuronal precursor cells in the mouse fetal hippocampus and these changes are associated with modifications in the protein levels of some cell cycle regulators and early differentiation markers. We fed C57 BL/6 mouse dams diets deficient or normal in choline content from days 12 to 17 of pregnancy, and then collected fetal brains on embryonic day 17. Using laser-capture micro-dissection we harvested cells from the ventricular and subventricular zones of Ammon's horn and from the prime germinal zone of the dentate gyrus (hippocampus). In the ventricular and subventricular zones from the choline-deficient group, we observed increased protein levels for kinase-associated phosphatase (Kap) and for p15(INK4b) (two cell cycle inhibitors). In the dentate gyrus, we observed increased levels of calretinin (an early marker of neuronal differentiation). In fetal brain from mothers fed a choline-deficient diet, DNA global methylation was decreased in the ventricular and subventricular zones of Ammon's horn. We also observed decreased gene-specific DNA methylation of the gene (Cdkn3) that encodes for Kap, correlating with increased expression of this protein. This was not the case for p15(INK4b) or calretinin (Cdkn2b and Calb2, respectively). These data suggest that choline deficiency-induced changes in gene methylation could mediate the expression of a cell cycle regulator and thereby alter brain development.

Animals↗
PubMed2006

Common genetic polymorphisms affect the human requirement for the nutrient choline.

Humans eating diets deficient in the essential nutrient choline can develop organ dysfunction. We hypothesized that common single nucleotide polymorphisms (SNPs) in genes involved in choline metabolism influence the dietary requirement of this nutrient. Fifty-seven humans were fed a low choline diet until they developed organ dysfunction or for up to 42 days. We tested DNA SNPs for allelic association with susceptibility to developing organ dysfunction associated with choline deficiency. We identified an SNP in the promoter region of the phosphatidylethanolamine N-methyltransferase gene (PEMT; -744 G-->C; rs12325817) for which 18 of 23 carriers of the C allele (78%) developed organ dysfunction when fed a low choline diet (odds ratio 25, P=0.002). The first of two SNPs in the coding region of the choline dehydrogenase gene (CHDH; +318 A-->C; rs9001) had a protective effect on susceptibility to choline deficiency, while a second CHDH variant (+432 G-->T; rs12676) was associated with increased susceptibility to choline deficiency. A SNP in the PEMT coding region (+5465 G-->A; rs7946) and a betaine:homocysteine methyltransferase (BHMT) SNP (+742 G-->A; rs3733890) were not associated with susceptibility to choline deficiency. Identification of common polymorphisms that affect dietary requirements for choline could enable us to identify individuals for whom we need to assure adequate dietary choline intake.

Choline↗
PubMed2006

Diethanolamine alters neurogenesis and induces apoptosis in fetal mouse hippocampus.

Diethanolamine (DEA) is present in many consumer products such as shampoo. Dermal administration of DEA diminishes hepatic stores of the essential nutrient choline, and we previously reported that dietary choline deficiency during pregnancy reduces neurogenesis and increases apoptosis in the hippocampus of fetal rats and mice. Therefore, DEA could also alter brain development. Timed-pregnant C57BL/6 mice were dosed dermally from gestation day 7 through 17 with DEA at 0, 20, 80, 160, 320, and 640 mg/kg body/day. At doses of DEA > 80 mg/kg body/day, we observed decreased litter size. In fetuses (embryonic day 17) collected from dams treated dermally with 80 mg/kg body/day DEA, we observed decreased neural progenitor cell mitosis at the ventricular surface of the ventricular zone of the hippocampus [to 56+/-14% (se) histone 3 (H3) phosphorylation as compared to controls; P < 0.01]. We also observed increased apoptosis in fetal hippocampus (to 170+/-10% of control measured using TUNEL and to 178+/-7% of control measured using activated caspase 3; P < 0.01). Thus, maternal exposure to DEA reduces the number of neural progenitor cells in hippocampus by two mechanisms, and this could permanently alter memory function in offspring of mothers exposed to this common ingredient of shampoos and soaps.

Administration, Topical↗
PubMed2006

Perinatal choline influences brain structure and function.

Choline is derived not only from the diet, but also from de novo synthesis. It is important for methyl-group metabolism, the formation of membranes, kidney function, and neurotransmission. When deprived of dietary choline, most adult men and postmenopausal women develop signs of organ dysfunction (fatty liver or muscle damage) and have a decreased capacity to convert homocysteine to methionine. Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain structure and function (memory is permanently enhanced in rodents exposed to choline during the latter part of gestation).

Brain↗
PubMed2006

Choline: critical role during fetal development and dietary requirements in adults.

Choline is an essential nutrient needed for the structural integrity and signaling functions of cell membranes; for normal cholinergic neurotransmission; for normal muscle function; for lipid transport from liver; and it is the major source of methyl groups in the diet. Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain and spinal cord structure and function and influencing risk for neural tube defects and lifelong memory function. Choline is derived not only from the diet, but from de novo synthesis as well. Though many foods contain choline, there is at least a twofold variation in dietary intake in humans. When deprived of dietary choline, most men and postmenopausal women developed signs of organ dysfunction (fatty liver or muscle damage), while less than half of premenopausal women developed such signs. Aside from gender differences, there is significant variation in the dietary requirement for choline that can be explained by very common genetic polymorphisms.

Brain↗
PubMed2006

Betaine supplementation and blood lipids: fact or artifact?

Betaine supplementation in humans has been shown to lower plasma homocysteine concentrations in modestly hyperhomocysteinemic patients. Betaine treatment is associated with increased plasma low-density-lipoprotein (LDL) cholesterol, suggesting that although betaine supplementation lowers homocysteine, a risk factor for cardiovascular disease, changes in blood lipids may have a counterbalancing effect. However, whether the betaine effect on LDL concentration is a clinically significant problem that should change treatment options or is simply an artifact needs further study.

Betaine↗
PubMed2005

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans.

Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0-25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement. The effects of the C677T and A1298C polymorphisms of the 5,10-methylene tetrahydrofolate reductase gene and the A80C polymorphism of the reduced folate carrier 1 gene were not statistically significant. The most remarkable finding was the strong association in premenopausal women of the 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele polymorphism with 15 times increased susceptibility to developing organ dysfunction on a low-choline diet.

Adult↗
PubMed2005

Maternal dietary choline availability alters the balance of netrin-1 and DCC neuronal migration proteins in fetal mouse brain hippocampus.

Alterations in maternal dietary choline availability during days 12-17 of pregnancy led to an increase in the level of immunoreactive netrin-1 and a decrease in the level of DCC protein in the developing fetal mouse brain hippocampus compared with controls. Changes in the expression of cell migration cues during development could account for some of the lifelong consequences of maternal dietary choline availability for cognitive and memory processes.

Animals↗
PubMed2005

Gene expression profiling in phosphatidylethanolamine N-methyltransferase knockout mice.

Choline is derived from the diet as well as from de novo methylation of phosphatidylethanolamine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). Pemt knockout mice have no endogenous synthesis of choline molecules. We previously reported that these mice have excess S-adenosylmethionine and hypermethylated DNA in brain, as well as increased mitosis in neural progenitor cells of the hippocampus in embryonic day 17 (E17) brain. In the present study, E17 fetal brains and adult brains were harvested and total RNA was extracted. In fetal brain, using gene expression profiling and Significance Analysis of Microarrays, we identified 107 significant genes with increased expression and 379 significant genes with decreased expression. In adult brain, we identified 381 significant genes with increased expression and 1037 significant genes with decreased expression. We observed significant changes in expression of genes regulating cell cycle (such as TP53, Fgf4, and Ing1), differentiation and neurogenesis (such as S100A4 and D14Ws), and phospholipid metabolism (such as Pip5k1a, Pitpn, and Pla2g6) as well as in a number of methyltransferase genes (including Gnmt). Some genes with expression known to be regulated by promoter methylation were suppressed in Pemt knockout brain (such as S100a4 and TP53). These findings are consistent with the biochemical changes that we previous reported in fetal brains from Pemt knockout mice. This is the first report of gene profiling in Pemt(-/-) mouse brain.

Animals↗
PubMed2005

Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load.

BACKGROUND: Elevated concentrations of homocysteine in blood may be an independent risk factor for the development of atherosclerosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to form methionine, as occurs in folate deficiency. A parallel pathway exists for methylation of homocysteine, in which choline, by way of betaine, is the methyl donor. OBJECTIVE: Our goal was to determine whether choline deficiency results in a decreased capacity to methylate homocysteine. DESIGN: C57BL/6J mice were fed diets containing 0, 10, or 35 mmol choline/kg diet for 3 wk. We then administered an oral methionine load to the animals and measured plasma homocysteine concentrations. Also, in a pilot study, we examined 8 men who were fed a diet providing 550 mg choline/d per 70 kg body weight for 10 d, followed by a diet providing almost no choline, until the subjects were clinically judged to be choline deficient or for <or=42 d. A methionine load was administered at the end of each dietary phase. RESULTS: Two hours after the methionine load, choline-deficient mice had plasma homocysteine concentrations twice those of choline-fed mice. Four hours after the methionine load, clinically choline-depleted men had plasma homocysteine concentrations that were 35% greater than those in men not choline depleted. CONCLUSION: These results suggest that choline, like folate, plays an important role in the metabolism of homocysteine in humans and that response to a methionine load may be useful when assessing choline nutriture.

Adult↗
PubMed2005

Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level.

Choline is an essential nutrient for humans that is used to synthesize membrane phospholipids and the neurotransmitter acetylcholine. Betaine, a metabolite of choline, functions as a methyl-group donor in the conversion of homocysteine to methionine, and is important for renal function. Accurate analysis of choline intake was previously not possible because the choline content of most foods was not known. Using new and recently published data on the concentrations of choline in common foods, we measured the choline content of diets consumed ad libitum by healthy adult volunteers housed in a clinical research center and compared these with estimates of choline intake derived from 3-d food records kept by subjects immediately before study enrollment. Mean choline intake in this subject population met or slightly exceeded the current Adequate Intake (AI) of 7 mg/(kg . d) set by the Institute of Medicine. Men and women consumed similar amounts of choline per day (8.4 and. 6.7 mg/kg, respectively; P = 0.11). Choline intakes estimated from the 3-d food records were significantly lower than this (when expressed as mg/kg, or as total mg, but not when normalized to energy intake), suggesting underreporting of food intake. Intake of betaine, which may spare choline utilization as a methyl-group donor, was 5.3 mg/(kg . d) in men and 4.7 mg/(kg . d) in women. Intake of folate, vitamin B-12, and methionine + cysteine, were similar and sufficient in all subjects. The current recommended AI for choline seems to be a good approximation of the actual intake of this nutrient.

Adult↗
PubMed2005

Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD).

Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT gene polymorphisms. DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT, which leads to a V175M substitution. V175M is a loss of function mutation, as determined by transiently transfecting McArdle-RH7777 cells with constructs of wild-type PEMT open reading frame or the V175M mutant. Met/Met at residue 175 (loss of function SNP) occurred in 67.9% of the NAFLD subjects and in only 40.7% of control subjects (P<0.03). For the first time we report that a polymorphism of the human PEMT gene (V175M) is associated with diminished activity and may confer susceptibility to NAFLD.

Adolescent↗