Maternal betaine supplementation during gestation enhances gene expression in skeletal muscle of newborn piglets

Betaine has been widely used in animal and human nutrition to promote muscle growth and performance, yet it remains unknown whether maternal betaine supplementation during gestation affects the metabolic characteristics of neonatal skeletal muscles. In the present study, feeding sows with betaine-supplemented diets throughout gestation significantly up-regulated the expression of mtDNA-encoded OXPHOS genes including COX1, COX2 and ND5, in the muscle of newborn piglets, which was associated with enhanced mitochondrial COX enzyme activity. Concurrently, maternal betaine supplementation increased plasma betaine concentration and muscle expression of methyl transfer enzymes, BHMT and GNMT in offspring piglets. Nevertheless, Dnmt3a was down-regulated at the level of both mRNA and protein, which was associated with hypomethylated mtDNA D-loop region. These results suggest that maternal betaine supplementation during gestation enhances expression of mtDNA-encoded genes through D-loop DNA hypomethylation in skeletal muscle of newborn piglets.

Jia, Y., et al., Maternal betaine supplementation during gestation enhances expression of mtDNA-encoded genes through D-loop DNA hypomethylation in skeletal muscle of newborn piglets. J Agric Food Chem, 2015.

Maternal betaine supplementation enhances betaine/methionine metabolism and DNA methyltransferase expression in the hippocampus of neonatal piglets

PURPOSE: The adequate supply of methyl donors is critical for the normal development of brain. The purpose of the present study was to investigate the effects of maternal betaine supplementation on hippocampal gene expression in neonatal piglets and to explore the possible mechanisms.
METHODS: Gestational sows were fed control or betaine-supplemented (3 g/kg) diets throughout the pregnancy. Immediately after birth, male piglets were killed, and the hippocampus was dissected for analyses. The mRNA abundance was determined by reverse transcription real-time polymerase chain reaction. Protein content was measured by Western blot, and DNA methylation was detected by methylated DNA immunoprecipitation assay.
RESULTS: Prenatal betaine supplementation did not alter the body weight or the hippocampus weight, but increased the hippocampal DNA content as well as the mRNA expression of proliferation-related genes. Prenatal betaine supplementation increased serum level of methionine (P < 0.05) and up-regulated (P < 0.05) the mRNA and protein expression of betaine-homocysteine methyltransferase, glycine N-methyltransferase and DNA methyltransferase 1 in the neonatal hippocampus. Hippocampal expression of insulin growth factor II (IGF2) and its receptors IGF1R and IGF2R were all significantly up-regulated (P < 0.05) in betaine-treated group, together with a significant activation (P < 0.01) of the downstream extracellular signal-regulated kinase 1/2. Moreover, the differentially methylated region (DMR) 1 and 2 on IGF2 locus was found to be hypermethylated (P < 0.05) in the hippocampus of betaine-treated piglets.
CONCLUSIONS: These results indicate that maternal betaine supplementation enhances betaine/methionine metabolism and DNA methyltransferase expression, causes hypermethylation of DMR on IGF2 gene, which was associated with augmented expression of IGF2 and cell proliferation/anti-apoptotic markers in the hippocampus of neonatal piglets.

Li, X., et al., Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions. Eur J Nutr, 2014.

Dietary betaine may help prevent NTDs

BACKGROUND: Low maternal intake of dietary choline and betaine (a choline derivative) has recently been investigated as a possible risk factor for neural tube defects (NTDs)
METHODS: This case-control study examined the NTD risk associated with choline and betaine in 409 Mexican-American women who gave birth during 1995 to 2000 in the 14-county border region of Texas RESULTS: Using data from the food frequency questionnaire and the lowest quartiles of intake as the reference categories, a protective association was suggested between higher intakes of choline and betaine and NTD risk although the 95% confidence intervals for all risk estimates included 1.0. For choline intake in the second, third, and fourth quartiles, adjusted odds ratios were 1.2, 0.80, and 0.89, respectively. Betaine appeared more protective with odds ratios of 0.62, 0.73, and 0.61, respectively, for the second, third, and fourth quartiles of intake.
CONCLUSION: Study findings suggest that dietary betaine may help to prevent NTDs.

Lavery, A.M., et al., Dietary intake of choline and neural tube defects in Mexican Americans. Birth Defects Res A Clin Mol Teratol, 2014

Supplementation with B12 vitamin, betaine or other methyl donors in addition to folic acid may further reduce NTD risk

Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.

Imbard, A., J.F. Benoist, and H.J. Blom, Neural tube defects, folic Acid and methylation. Int J Environ Res Public Health, 2013. 10(9): p. 4352-89

Maternal methyl metabolism, offspring DNA methylation, and epigenetic consequences on later disease susceptibility

Evidence is growing for the long-term effects of environmental factors during early-life on later disease susceptibility. It is believed that epigenetic mechanisms (changes in gene function not mediated by DNA sequence alteration), particularly DNA methylation, play a role in these processes. This paper reviews the current state of knowledge of the involvement of C1 metabolism and methyl donors and cofactors in maternal diet-induced DNA methylation changes in utero as an epigenetic mechanism. Methyl groups for DNA methylation are mostly derived from the diet and supplied through C1 metabolism by way of choline, betaine, methionine or folate, with involvement of riboflavin and vitamins B6 and B12 as cofactors. Mouse models have shown that epigenetic features, for example DNA methylation, can be altered by periconceptional nutritional interventions such as folate supplementation, thereby changing offspring phenotype. Evidence of early nutrient-induced epigenetic change in human subjects is scant, but it is known that during pregnancy C1 metabolism has to cope with high fetal demands for folate and choline needed for neural tube closure and normal development. Retrospective studies investigating the effect of famine or season during pregnancy indicate that variation in early environmental exposure in utero leads to differences in DNA methylation of offspring. This may affect gene expression in the offspring. Further research is needed to examine the real impact of maternal nutrient availability on DNA methylation in the developing fetus.

Dominguez-Salas, P., et al., Maternal nutritional status, C(1) metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc, 2012. 71(1): p. 154-65

Maternal BHMT polymorphism 742G>A is associated with decreased risk of having a Down syndrome child

Down syndrome (DS) is the most common form of mental retardation of genetic etiology. Several polymorphisms in genes involved with the folic acid cycle have been associated to the risk of bearing a DS child; however, the results are controversial. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme of folate pathway, and catalyzes the remethylation of homocysteine into methionine. Recent studies suggest that the polymorphism BHMT 742G>A may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 94 mothers of DS infants (DSM) and 134 control mothers (CM) for this polymorphism through PCR-RFLP, and found significant differences for both BHMT 742G>A genotype (P = 0.04) and allele (P = 0.03) frequencies between DSM and CM. The observed genotypic frequencies were GG = 0.45; GA = 0.45 and AA = 0.10 in CM, and GG = 0.54; GA = 0.38 and AA = 0.02 in DSM. Allelic frequencies were G = 0.68 and A = 0.32 in CM and G = 0.78 and A = 0.22 in DSM. The presence of the mutant BHMT 742 A allele decreases 40 % the risk of bearing a DS child (OR = 0.61; 95 % CI: 0.40-0.93; P = 0.03), and the risk is diminished up to >80 % in association with the homozygous genotype (OR = 0.17; 95 % CI: 0.04-0.80; P = 0.01). Our results indicate that women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.

Amorim, M.R., et al., Betaine-homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population. Mol Biol Rep, 2013

Betaine may be used as a methyl-donor during fetal life

OBJECTIVE: Methylation metabolism is essential for fetus development. However, normative data for amniotic fluid (AF) concentrations of methylation metabolites at different gestational ages are lacking. We aimed to determine in AF reference values of 14 intermediates involved in methylation.
METHODS: 268 AFs sampled between 14 and 39 weeks of gestation (WG) were retrospectively selected in our AF bank. Next, we measured methionine-cycle intermediates (S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), total homocysteine, methionine, methyl malonic acid) and methyldonors and methylacceptors (betaine, dimethylglycine, sarcosine, free and total choline, free and total ethanolamine, creatine, guanidinoacetate) by liquid chromatography coupled with tandem mass spectrometry.
RESULTS: Reference ranges according to gestational age were determined for each parameter. Strong correlations between metabolites directly connected in their metabolic pathway and between total homocysteine and betaine were observed.
CONCLUSION: Methionine, an essential amino-acid required for protein synthesis is the only parameter that dramatically decreases with gestational age. The AdoMet/AdoHcy ratio exponentially increases from 25 WG, which could reflect increasing methylation capacities. The negative correlation between betaine and total homocysteine together with a constant betaine to dimethylglycine ratio during gestation suggest that betaine may be used as a methyl-donor during fetal life.

Imbard, A., et al., Methylation metabolites in amniotic fluid depend on gestational age. Prenat Diagn, 2013

Low folate status enhances pregnancy changes in plasma betaine and dimethylglycine concentrations and the association between betaine and homocysteine

BACKGROUND: Folate, choline, and betaine participate in homocysteine metabolism. It is not known whether they interact during pregnancy. OBJECTIVE: The objective was to investigate how folate status affects choline, betaine, and dimethylglycine during pregnancy. 

DESIGN: Fasting plasma folate, cobalamin, free choline, betaine, dimethylglycine, and total homocysteine (tHcy) were measured longitudinally at >12, 15, 24-27, and 34 gestational weeks (GW); at labor (nonfasting); and in the cord in participants (n = 522) from the Reus-Tarragona Birth Cohort (NUTricio i Creixement Intrauteri Retardat phase). Timing, dose, and duration of folic acid supplement use were recorded. Folate status was classified as below (low) or above (high) median plasma folate at baseline (27.6 nmol/L) and at 24-27 GW (11.4 nmol/L). Associations between folate or betaine with tHcy were investigated by using multiple linear regression analysis. 

RESULTS: Plasma betaine decreased by 34.8% (1.0%) throughout pregnancy, and dimethylglycine increased by 39.7% (2.7%) between 24-27 GW and labor (all P < 0.001). Low folate status was associated with a higher dimethylglycine/betaine ratio from 15 GW and with lower plasma betaine and higher dimethylglycine from 24 to 27 GW, for the rest of pregnancy, compared with high status. Regression analysis showed that by 24-27 GW, both plasma folate and betaine were inversely associated with tHcy when folate status was low and that the association between betaine and tHcy depended on folate status at 24-27 and 34 GW (interaction terms: P < 0.001 and P < 0.01). Betaine was inversely associated with tHcy at labor regardless of folate status. 

CONCLUSION: Low folate status enhances the reduction in betaine and the increase in dimethylglycine during pregnancy and strengthens the association between betaine and tHcy. This trial was registered at clinicaltrials.gov as NCT01778205. 

Fernandez-Roig, S., et al., Low folate status enhances pregnancy changes in plasma betaine and dimethylglycine concentrations and the association between betaine and homocysteine. Am J Clin Nutr, 2013

Lower seasonal maternal dietary betaine intake and resultant lower blood levels correlates with previously reported reduced DNA methylation in offspring

BACKGROUND: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian rainy season.

OBJECTIVE:The objective was to understand the seasonality of DNA methylation patterns in rural Gambian women. We studied natural variations in dietary intake of nutrients involved in methyl-donor pathways and their effect on the respective metabolic biomarkers.

DESIGN:In 30 women of reproductive age (18-45 y), we monitored diets monthly for 1 y by using 48-h weighed records to measure intakes of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12. Blood biomarkers of these nutrients, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), homocysteine, cysteine, and dimethylglycine were also assessed monthly.

RESULTS:Dietary intakes of riboflavin, folate, choline, and betaine varied significantly by season; the most dramatic variation was seen for betaine. All metabolic biomarkers showed significant seasonality, and vitamin B-6 and folate had the highest fluctuations. Correlations between dietary intakes and blood biomarkers were found for riboflavin, vitamin B-6, active vitamin B-12 (holotranscobalamin), and betaine. We observed a seasonal switch between the betaine and folate pathways and a probable limiting role of riboflavin in these processes and a higher SAM/SAH ratio during the rainy season.

CONCLUSIONS:Naturally occurring seasonal variations in food-consumption patterns have a profound effect on methyl-donor biomarker status. The direction of these changes was consistent with previously reported differences in methylation of metastable epialleles. This trial was registered at www.clinicaltrials.gov as NCT01811641.

Dominguez-Salas, P., et al., DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr, 2013

Increased risk of low birth weight with increased umbilical choline and betaine in venous UC blood

Background: Low birth weight (LBW) is associated with increased morbidity and mortality for the newborn and risk of chronic disease in adulthood. Choline plays an essential role in the integrity of cell membranes, methylation reactions and memory development. We examined whether choline, betaine and dimethylglycine (DMG) concentrations were associated with LBW in Dutch women.
Methods: Blood was sampled from umbilical cords (UC) at delivery in singleton pregnancies (n=1126). Maternal blood was sampled at 30-34 weeks of gestational age (n=366). We calculated birth weights standardized for gestational age (SBW) and defined LBW as SBW </= 2500 grams.
Results: Maternal concentrations were lower compared to UC concentrations and not associated with birth weight. UC choline and betaine were inversely associated with birth weight (beta= -60 (-89, -31) and beta= -65 (-94, -36)), whereas UC DMG was positively associated with birth weight (beta= 35 (6.1, 63)). Odds ratios for LBW were 4.12 (1.15, 14.78) , 5.68 (1.24, 25.91), and 0.48 (0.09, 2.65) for the highest UC choline, betaine and DMG quartile respectively compared to the lowest quartiles.
Conclusions: We observed an increased risk of low birth weight with increased umbilical choline and betaine in venous UC blood. These results might reflect a change in choline consumption or metabolism or a disturbed placental function.

Hogeveen, M., et al., Umbilical choline and related methylamines betaine and dimethylglycine in relation to birth weight. Pediatr Res, 2013

Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice

Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1(-/-) offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects.

Billington, C.J., Jr., et al., Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice. J Nutr, 2013

Maternal intake of methyl-donor nutrients and child cognition

Methyl-donor nutrients are substrates for methylation reactions involved in neurodevelopment processes. The role of maternal intake of these nutrients on cognitive performance of the offspring is poorly understood. We examined the associations of maternal intake of folate, vitamin B12, choline, betaine and methionine during the first and second trimesters of pregnancy, with tests of cognitive performance in the offspring at 3 years of age using data from 1210 participants in Project Viva, a prospective pre-birth cohort study in Massachusetts. We assessed nutrient intake with the use of food frequency questionnaires. Children's cognition at age 3 years was evaluated with the Peabody Picture Vocabulary Test III (PPVT-III) and visual-motor skills with the Wide Range Assessment of Visual Motor Abilities test. In multivariable models adjusting for potential sociobehavioural and nutritional confounders, for each 600 microg/day increment in total folate intake during the first trimester, PPVT-III score at age 3 years was 1.6 points [95% confidence interval (CI) 0.1, 3.1; P = 0.04] higher. There was a weak inverse association between vitamin B12 intake during the second trimester and PPVT-III scores [-0.4 points per 2.6 microg/day; 95% CI -0.8, -0.1; P = 0.01]. We did not find associations between choline, betaine or methionine and cognitive outcomes at this age. Results of this study suggest that higher intake of folate in early pregnancy is associated with higher scores on the PPVT-III, a test of receptive language that predicts overall intelligence, at age 3 years.

In unadjusted analyses, intake of folate and betaine during the first or second trimester was directly related to PPVT-III scores. After adjustment for potential socio-economic, educational and dietary confounders, however, the associations with both nutrients were attenuated and only the relationship between folate intake during the first trimester and PPVT-III scores remained statistically significant.

Villamor, E., et al., Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr Perinat Epidemiol, 2012. 26(4): p. 328-35.

Non-targeted analyses of animal plasma: betaine and choline represent the nutritional and metabolic status

Simple liquid chromatography–mass spectrometry (LC-MS) was applied to non-targeted metabolic analyses to discover new metabolic markers in animal plasma. Principle component analysis (PCA) and partial least squares–discriminate analysis (PLS-DA) were used to analyse LC-MS multivariate data. PCA clearly generated two separate clusters for artificially induced diabetic mice and healthy control mice. PLS-DA of time-course changes in plasma metabolites of chicks after feeding generated three clusters (pre- and immediately after feeding, 0.5–3 h after feeding and 4 h after feeding). Two separate clusters were also generated for plasma metabolites of pregnant Angus heifers with differing live-weight change profiles (gaining or losing). The accompanying PLS-DA loading plot detailed the metabolites that contribute the most to the cluster separation. In each case, the same highly hydrophilic metabolite was strongly correlated to the group separation. The metabolite was identified as betaine by LC-MS/MS. This result indicates that betaine and its metabolic precursor, choline, may be useful biomarkers to evaluate the nutritional and metabolic status of animals.

Katayama, K., et al., Non-targeted analyses of animal plasma: betaine and choline represent the nutritional and metabolic status. J Anim Physiol Anim Nutr (Berl), 2011. 5 Nov.

Betaine homocysteine methyltransferase is active in the mouse blastocyst and promotes inner cell mass development

Methyltransferases are an important group of enzymes with diverse roles that include epigenetic gene regulation. The universal donor of methyl groups for methyltransferases is S-adenosylmethionine (AdoMet), which in most cells is synthesized using methyl groups carried by a derivative of folic acid. Another mechanism for AdoMet synthesis uses betaine as the methyl donor via the enzyme betaine-homocysteine methyltransferase (BHMT, EC 2.1.1.5), but it has been considered to be significant only in liver. Here, we show that mouse preimplantation embryos contain endogenous betaine; Bhmt mRNA is first expressed at the morula stage; BHMT is abundant at the blastocyst stage but not other preimplantation stages, and BHMT activity is similarly detectable in blastocyst homogenates but not those of two-cell or morula stage embryos. Knockdown of BHMT protein levels and reduction of enzyme activity using Bhmt-specific antisense morpholinos or a selective BHMT inhibitor resulted in decreased development of embryos to the blastocyst stage in vitro and a reduction in inner cell mass cell number in blastocysts. The detrimental effects of BHMT knockdown were fully rescued by the immediate methyl-carrying product of BHMT, methionine. A physiological role for betaine and BHMT in blastocyst viability was further indicated by increased fetal resorption following embryo transfer of BHMT knockdown blastocysts versus control. Thus, mouse blastocysts are unusual in being able to generate AdoMet not only by the ubiquitous folate-dependent mechanism but also from betaine metabolized by BHMT, likely a significant pool of methyl groups in blastocysts.
Lee, M.B., et al., Betaine homocysteine methyltransferase is active in the mouse blastocyst and promotes inner cell mass development. J Biol Chem, 2012. 287(39): p. 33094-103

Women who developed gestational diabetes had lower plasma betaine

This work describes an exploratory NMR metabonomic study of second trimester maternal urine and plasma, in an attempt to characterize the metabolic changes underlying prenatal disorders and identify possible early biomarkers. Fetal malformations have the strongest metabolic impact in both biofluids, suggesting effects due to hypoxia (leading to hypoxanthine increased excretion) and a need for enhanced gluconeogenesis, with higher ketone bodies (acetone and 3-hydroxybutyric acid) production and TCA cycle demand (suggested by glucogenic amino acids and cis-aconitate overproduction). Choline and nucleotide metabolisms also seem affected and a distinct plasma lipids profile is observed for mothers with fetuses affected by central nervous system malformations. Urine from women who subsequently develop gestational diabetes mellitus exhibits higher 3-hydroxyisovalerate and 2-hydroxyisobutyrate levels, probably due to altered biotin status and amino acid and/or gut metabolisms (the latter possibly related to higher BMI values). Other urinary changes suggest choline and nucleotide metabolic alterations, whereas lower plasma betaine and TMAO levels are found. Chromosomal disorders and pre-preterm delivery groups show urinary changes in choline and, in the latter case, in 2-hydroxyisobutyrate. These results show that NMR metabonomics of maternal biofluids enables the noninvasive detection of metabolic changes associated to prenatal disorders, thus unveiling potential disorder biomarkers.

Diaz, S.O., et al., Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. J Proteome Res, 2011. 10(8): p. 3732-42.

Amniotic fluid metabolites

This study aimed to establish and compare normative metabolite concentrations in 2nd and 3rd trimester human amniotic fluid samples in an effort to reveal metabolic biomarkers of fetal health and development.

21 metabolite concentrations were compared between 2nd and 3rd trimester amniotic fluid samples using (1)H high resolution magic angle spinning (HR-MAS) spectroscopy. 16 of 21 metabolite concentrations differed significantly between 2nd and 3rd trimester groups. Betaine and creatinine concentrations increased significantly, while glucose, citrate, pyruvate, and numerous amino acid concentrations decreased significantly with advancing gestation.

These results provide key normative data for 2nd and 3rd trimester amniotic fluid metabolite concentrations and provide the foundation for future development of magnetic resonance spectroscopy (MRS) biomarkers to evaluate fetal health and development.

Cohn et al (2009). "Quantitative metabolic profiles of 2nd and 3rd trimester human amniotic fluid using (1)H HR-MAS spectroscopy." Magma. Epub Sept.

One carbon metabolism and birth defects

The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B6, vitamin B12, riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD).

They analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants.

TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

Robitaille et al (2009). "Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: Data from the National Birth Defects Prevention Study, 1997-2003." Birth Defects Research Part A: Clinical and Molecular Teratology. March 1 Epub.

Metabolic Syndrome, CVD Risk & Related Epidemiological Studies

Konstantinova et al (2008) "Divergent Associations of Plasma Choline and Betaine with Components of Metabolic Syndrome in Middle Age and Elderly Men and Women"

This epidemiological study found that high serum betaine was associated with low:

- serum non-HDL cholesterol
- triglycerides
- BMI
- percent body fat
- waist circumference
- systolic and diastolic blood pressure
- smoking

and associated with high:

- HDL cholesterol
- physical activity

Thus favorable cardiovascular and metabolic syndrome risk factors were associated with high betaine concentrations.

Papers 2004-7:

Shaw et al (2004) "Periconceptional dietary intake of choline and betaine and neural tube defects in offspring."

Yagisawa et al (2004). "Effects of intravenous betaine on methionine-loading-induced plasma homocysteine elevation in rats." J Nutr Biochem 15(11): 666-71.

Schwahn et al (2005) "Betaine is a determinant of plasma lipids in men."

Melse-Boonstra et al (2005). "Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations." Am J Clin Nutr 81(6): 1378-1382.

Ueland et al (2005). "Betaine: a key modulator of one-carbon metabolism and homocysteine status." Clin Chem Lab Med 43(10): 1069-75.

Olthof et al (2005) "Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans."

Velzing-Aarts et al (2005). "Plasma choline and betaine and their relation to plasma homocysteine in normal pregnancy." Am J Clin Nutr 81(6): 1383-1389.

Verhoef and de Groot (2005). "Dietary determinants of plasma homocysteine concentrations." Semin Vasc Med 5(2): 110-23.

Olthof and Verhoef (2005) "Effects of betaine intake on plasma homocysteine concentrations and consequences for health."

Olthof et al (2006) "Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers."

Olthof et al (2006) "Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: a randomized trial."

Iqbal et al (2006) "Betaine, a novel antithrombotic agent for effective management of peripheral arterial occlusive diseases."

Iqbal et al (2006) "Betaine induced release of tissue factor pathway inhibitor and nitric oxide: implications in the management of cardiovascular disease."

Schwab et al (2006) "Orally Administered Betaine Has an Acute and Dose-Dependent Effect on Serum Betaine and Plasma Homocysteine Concentrations in Healthy Humans."

Cho et al (2006) "Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study."

Francois H. T. Duong (2006). "S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro." Hepatology 43(4): 796-806.

Zeisel (2006). "Betaine supplementation and blood lipids: fact or artifact?" Nutr Rev 64(2 Pt 1): 77-9.

Bidulescu et al (2007) "Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study."

Schwahn et al (2007) "Betaine supplementation improves the atherogenic risk factor profile in a transgenic mouse model of hyperhomocysteinemia."

Chiuve et al (2007). "The association between betaine and choline intakes and the plasma concentrations of homocysteine in women."

Dalmeijer et al (2007). "Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women."

Wallace et al (2008) "Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study."