Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum

Albright, Craig D.; Friedrich, Claudia B.; Brown, Elliott C.; Mar, Mei Heng; Zeisel, Steven H.

doi:10.1016/s0165-3806(99)00057-7

Cited by 138 publications

(109 citation statements)

References 31 publications

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“…In preclinical studies, the period of choline administration ranged from 10 to 20 d, which is equivalent to years in human development. The results from these studies suggest that choline's effects are due to structural changes in brain development (3) (e.g., increased hippocampal neurogenesis (41)(42)(43). However, choline is hypothesized to have multiple mechanisms of action including acute changes in cholinergic activity, changes in cellular membranes and signaling pathways, and epigenetic modification of gene expression (44,45).…”

Section: Discussionmentioning

confidence: 99%

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Nguyen

Risbud

Mattson

et al. 2016

The American Journal of Clinical Nutrition

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Background: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. Objective: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. Design: In the current study, which was a randomized, doubleblind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5-10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Results: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Conclusions: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5-10 y old) children with FASDs. This research provides important information about choline's therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299.Am J Clin Nutr 2016;104:1683-92.

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Section: Discussionmentioning

confidence: 99%

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Nguyen

Risbud

Mattson

et al. 2016

The American Journal of Clinical Nutrition

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“…Therefore, a reduction of its expression should lead to lower islet-cell proliferation. TOAD-64 is present in fetal islets although it is described as a marker of commitment to neuronal differentiation during fetal development [100]. In low-pro-tein-diet islets TOAD-64 was down-regulated.…”

Section: Discussionmentioning

confidence: 99%

“…In low-pro-tein-diet islets TOAD-64 was down-regulated. Interestingly, maternal dietary choline deficiency decreases the rate of mitosis and increases the number of apoptotic cells associated with decreased expression of TOAD-64 in the progenitor neuroepithelium adjacent to the septum [100].…”

Section: Discussionmentioning

confidence: 99%

Intrauterine programming of fetal islet gene expression in rats?effects of maternal protein restriction during gestation revealed by proteome analysis

et al. 2003

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Aims/hypothesis. Fetal undernutrition can result in intrauterine growth restriction and increased incidence of Type 2 diabetes mellitus. Intrauterine malnutrition in form of an isocaloric low-protein diet given to female rats throughout gestation decreases islet-cell proliferation, islet size and pancreatic insulin content, while increasing the apoptotic rate and sensitivity to nitrogen oxide and interleukin-1β. Hence, the influence of a lowprotein diet on the development of beta-cells and islets could also be of interest for the pathogenesis of Type 1 and Type 2 diabetes mellitus. We hypothesise that the effects of a low-protein diet in utero are caused by intrauterine programming of beta-cell gene expression. Methods. Pregnant Wistar rats were fed a low-protein diet (8% protein) or a control diet (20% protein) throughout gestation. At day 21.5 of gestation fetal pancreata were removed, digested and cultured for 7 days. Neoformed islets were collected and analysed by proteome analysis comprising 2-dimensional gel electrophoresis and mass spectrometry. Results.A total of 2810 different protein spots were identified, 70 of which were changed due to the lowprotein diet. From 45 of the changed protein spots, identification was obtained by mass spectrometry (64% success rate). Proteins induced by the low-protein diet were grouped according to their biological functions, e.g. cell cycle and differentiation, protein synthesis and chaperoning. Conclusions/interpretation. Our study offers a possible explanation of the alterations induced by a lowprotein diet in islets. It shows that in Wistar rats the intrauterine milieu could program islet gene expression in ways unfavourable for the future of the progeny. This could be important for our understanding of the development of Type 1 and Type 2 diabetes mellitus. [Diabetologia (2003[Diabetologia ( ) 46:1497[Diabetologia ( -1511

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“…37 More choline (about 3 times the dietary levels) during days 11 to 18 of gestation results in increased cell proliferation and decreased apoptosis in rodent fetal hippocampal progenitor cells. 38,39 Morphological alterations occur in the brain after choline supplementation during fetal life, including larger soma and increased numbers of primary and secondary basal dendritic branches. 40,41 The brief exposure to extra choline in utero and subsequent changes in hippocampal structure result in enhanced long-term potentiation, (an electrophysiological property of the hippocampus), 42-44 and enhanced visuospatial and auditory memory (by as much as 30%) throughout the lifespan.…”

Section: Choline Availability Alters Brain Hippocampal Developmentmentioning

confidence: 99%

The fetal origins of memory: The role of dietary choline in optimal brain development

Zeisel

2006

The Journal of Pediatrics

195

140

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Fetal nutrition sets the stage for organ function in later life. In this review we discuss the fetal and neonatal origins of brain function. Numerous research observations point to the importance of choline for the developing fetus and neonate. This essential nutrient is involved in 1-carbon metabolism and is the precursor for many important compounds, including phospholipids, acetylcholine, and the methyl donor betaine. Dietary intake of choline by the pregnant mother and later by the infant directly affects brain development and results in permanent changes in brain function. In rodents, perinatal supplementation of choline enhances memory and learning functions, changes that endure across the lifespan. Conversely, choline deficiency during these sensitive periods results in memory and cognitive deficits that also persist. Furthermore, recent studies suggest that perinatal choline supplementation can reduce the behavioral effects of prenatal stress and the cognitive effects of prenatal alcohol exposure in offspring. The likely mechanism for these effects of choline involves DNA methylation, altered gene expression, and associated changes in stem cell proliferation and differentiation. The currently available animal data on choline and hippocampal development are compelling, but studies are needed to detrermine whether the same is true in humans.There is a growing body of evidence indicating that fetal and perinatal nutrition and growth influence organ function in adult life (eg, blood pressure, 1 heart disease, 2 diabetes 3 ). Evidence also indicates that fetal and perinatal nutrition influence brain function in later life. Iron, 4 zinc, 5 and folate 6 nutriture in the fetus have been shown to alter brain development, and there is compelling data showing that another important nutrient, choline, is essential for brain formation. The human requirement for choline was officially recognized with the establishment of adequate intake recommendations by the Institute of Medicine in 1998 7 (adequate intake for infants age 0 to 6 months, 18 mg/kg/day). Choline is required for the structural integrity and signaling functions of cell membranes, methyl group metabolism, and neurotransmitter synthesis. 8 Some of the choline needed to sustain normal organ function is synthesized de novo, mainly in the liver, 9 when phosphatidylethanolamine is methylated by phosphatidylethanolamine N-methyltransferase (PEMT) to form phosphatidylcholine. However, this mechanism does not always meet the demands for choline, and humans eating diets deficient in choline develop fatty liver, liver damage, and muscle damage. 10,11 In this review, the main focus is on choline's role in brain development and function during the perinatal period.

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Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum

Cited by 138 publications

References 31 publications

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Intrauterine programming of fetal islet gene expression in rats?effects of maternal protein restriction during gestation revealed by proteome analysis

The fetal origins of memory: The role of dietary choline in optimal brain development

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