Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Beaudin, Anna E.; Stover, Patrick J.

doi:10.1002/bdrc.20100

Cited by 126 publications

(129 citation statements)

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“…Periconceptual folate deficiency has long been recognised as a risk factor in the incidence of neural tube defects in pregnant women [48], and in the pregnant mouse folate deficiency increases the frequency of developmental anomalies and spontaneous resorption [49]. Choline deficiency also increases the risk of neural tube defects and has long-term effects on brain development and cognitive function [50,51,52].…”

Section: Discussionmentioning

confidence: 99%

Pre- and Postnatal Methyl Deficiency in the Rat Differentially Alters Glucose Homeostasis

Smith¹,

Konycheva²,

Dziadek³

et al. 2011

Lifestyle Genomics

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Background/Aims: Early-life methyl-donor deficiency is implicated in growth restriction and later-life development of type 2 diabetes mellitus. We ascertained whether dietary methyl-donor deficiency in the mother during pregnancy or during postweaning growth in the rat would impair glucose homeostasis, insulin secretion and pancreatic endocrine development in young adults. Methods: Effects of maternal methyl deficiency (90% deficiency in methionine, folate and choline) were compared with those of postweaning methyl deficiency and with control diets for effects on growth, impaired glucose tolerance, insulin secretion and pancreas development in offspring. Studies focussed on male offspring, which have been shown more susceptible to early-life influences on later disease development. Results: Prenatal methyl deficiency delayed delivery, restricted birthweight by 22%, reduced litter size by 33% and increased offspring mortality to 23% shortly after birth. It reduced relative endocrine pancreatic mass in adult male offspring to 46% of endocrine mass in controls, but only mildly impaired their glucose tolerance and insulin secretion. In contrast, postweaning methyl deficiency restricted growth of male rats and reduced relative pancreatic endocrine mass (–40%), but improved their glucose tolerance, despite decreased insulin secretion. Conclusion: It is clear that the global undernutrition (UN) during pregnancy in rodents alters glucose metabolism in adult offspring. It has been hypothesised that alterations in epigenetic mechanisms may underlie this phenotype. However, removing all methyl donors during pregnancy, which are essential for epigenetic processes in development, did not cause any alteration in glucose metabolism in offspring as seen in the global UN model.

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Section: Discussionmentioning

confidence: 99%

Pre- and Postnatal Methyl Deficiency in the Rat Differentially Alters Glucose Homeostasis

Smith¹,

Konycheva²,

Dziadek³

et al. 2011

Lifestyle Genomics

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“…It has been suggested that folate supplements improve fetal development by increasing the recycling of homocysteine to methionine through the methionine cycle ( Fig. 1) (1,2,8).…”

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confidence: 99%

Effects of methyl-deficient diets on methionine and homocysteine metabolism in the pregnant rat

Wilson

Holtrop

Calder

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Rees WD. Effects of methyl-deficient diets on methionine and homocysteine metabolism in the pregnant rat. Am J Physiol Endocrinol Metab 302: E1531-E1540, 2012. First published March 27, 2012 doi:10.1152/ajpendo.00668.2011.-Although the importance of methyl metabolism in fetal development is well recognized, there is limited information on the dynamics of methionine flow through maternal and fetal tissues and on how this is related to circulating total homocysteine concentrations. Rates of homocysteine remethylation in maternal and fetal tissues on days 11, 19, and 21 of gestation were measured in pregnant rats fed diets with limiting or surplus amounts of folic acid and choline at two levels of methionine and then infused with L-[1-13 C, 2 H3-methyl]methionine. The rate of homocysteine remethylation was highest in maternal liver and declined as gestation progressed. Diets deficient in folic acid and choline reduced the production of methionine from homocysteine in maternal liver only in the animals fed a methionine-limited diet. Throughout gestation, the pancreas exported homocysteine for methylation within other tissues. Little or no methionine cycle activity was detected in the placenta at days 19 and 21 of gestation, but, during this period, fetal tissues, especially the liver, synthesized methionine from homocysteine. Greater enrichment of homocysteine in maternal plasma than placenta, even in animals fed the most-deficient diets, shows that the placenta did not contribute homocysteine to maternal plasma. Methionine synthesis from homocysteine in fetal tissues was maintained or increased when the dams were fed folate-and choline-deficient methionine-restricted diets. This study shows that methyl-deficient diets decrease the remethylation of homocysteine within maternal tissues but that these rates are protected to some extent within fetal tissues.folate; choline; fetal development; stable isotopes NUMEROUS LARGE-SCALE CLINICAL trials have clearly established the value of folic acid supplements in pregnancy (23). In addition to a marked reduction in the frequency of neural tube defects and other congenital malformations of the fetus (7, 13), improved folate status is also associated with enhanced fetal growth (17). Elevated plasma total (t-) homocysteine concentration, a marker of changes in methyl metabolism, is also recognized as a risk factor for a number of adverse pregnancy outcomes in humans (11,24,27). It has been suggested that folate supplements improve fetal development by increasing the recycling of homocysteine to methionine through the methionine cycle (Fig. 1) (1, 2, 8).The relationship between the availability of folic acid and associated methyl donors in the maternal diet and the flow through the methionine cycle in the tissues of the mother and the developing fetus is poorly quantified. Studies of pregnant rats show that methyl-deficient diets low in folic acid, choline, and methionine increase t-homocysteine concentrations in maternal and fetal plasma (9). While the enzymes of the methionin...

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“…Entre los factores ambientales, la cantidad de ácido fólico proporcionada por la dieta, desempeña un papel importante en la determinación del riesgo de DTNs (Bloom et al;Beaudin et al, 2007). Así, se ha demostrado que la suplementación de la dieta materna con AF durante el período periconcepcional y/o durante la gravidez, reduce la frecuencia de los DTNs u ocurrencia de tener un hijo con defectos de cierre del tubo neural (Czeizel & Dudás, 1992;Berry et al, 1999).…”

Section: Determinación Genética De Los Defectos Del Tubo Neural (Dtns)unclassified

Malformaciones Congénitas: Aspectos Generales y Genéticos

Rojas

Walker

2012

Int. J. Morphol.

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RESUMEN:Los defectos del desarrollo se pueden deber a malformaciones congénitas, deformaciones o disrupciones. El 10% de las malformaciones se atribuyen a causas ambientales el 25% a factores genéticos y el 65% a factores desconocidos probablemente de orden multifactorial. Existe un período de mayor susceptibilidad frente a los teratógenos que corresponde a la etapa donde se están formando la mayoría de los órganos y sistemas. La ingestión de plantas teratogénicas puede dar lugar a anomalías congénitas en los fetos de animales. Los pesticidas como DDT, la contaminación de las aguas por mercurio y los disruptores endocrinos afectan la embriogénesis de las distintas especies del reino animal. También se consideran como factores causantes de malformaciones a los agentes ambientales infecciosos y a algunos medicamentos. Los agentes físicos como los aumentos de temperatura, las condiciones de hipoxia y las radiaciones afectan a distintos organismos, desde los peces al ser humano. La genética de las malformaciones ha sido difícil de establecer, principalmente porque la mayor parte de ellas se caracteriza por presentar manifestaciones fenotípicas diversas, que en muchos casos aparentemente no están relacionadas y que son variables para los individuos afectados. Por otra parte, los estudios realizados indican que frecuentemente, en la determinación genética de las malformaciones participan varios genes y las interacciones de éstos con el ambiente, aunque determinaciones monogénicas se han podido establecer para unos pocos casos. Ilustramos aquí estos dos tipos contrastantes de determinación genética, a través de la descripción de los factores genéticos que estarían involucrados en los defectos del tubo neural y en el síndrome de CHARGE, respectivamente. PALABRAS CLAVE: Malformaciones congénitas; Factores ambientales y genéticos; Defectos del tubo neural; Síndrome de CHARGE. ASPECTOS GENERALESLas anomalías congénitas incluyen no solo evidentes defectos estructurales, sino también defectos microscó-picos, errores del metabolismo, trastornos fisiológicos y anomalías celulares y moleculares. Las anomalías mayores comprometen la función y la aceptabilidad social, las anomalías menores, en cambio, no representan problemas mé-dicos ni cosméticos.Los defectos al nacer se pueden deber a: 1) malformaciones congénitas que corresponden a defectos de los mecanismos biológicos del desarrollo tales como proliferación, diferenciación, migración celular, apoptosis, inducción, transformaciones epitelio-mesenquimáticas e interacciones tisulares; 2) deformaciones, se utiliza para designar la alteración de la forma o la posición de una estructura que se había formado normalmente, como es el caso de la tortíco-lis congénita del esternocleidomastoídeo (cuello torcido), las deformaciones de los pies, la luxación congénita de cadera y la escoliosis postural congénita; 3) disrupciones, este término se ocupa para indicar la ruptura de un tejido previamente normal, por ejemplo las fisuras faciales atípicas.Muchos defectos del desarrollo no se expr...

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Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Cited by 126 publications

References 201 publications

Pre- and Postnatal Methyl Deficiency in the Rat Differentially Alters Glucose Homeostasis

Pre- and Postnatal Methyl Deficiency in the Rat Differentially Alters Glucose Homeostasis

Effects of methyl-deficient diets on methionine and homocysteine metabolism in the pregnant rat

Malformaciones Congénitas: Aspectos Generales y Genéticos

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