Next Article in Journal
The Role of the Anabolic Properties of Plant- versus Animal-Based Protein Sources in Supporting Muscle Mass Maintenance: A Critical Review
Next Article in Special Issue
Functional Expression of Choline Transporters in the Blood–Brain Barrier
Previous Article in Journal
Hot Water Extract of Curcuma longa L. Improves Serum Inflammatory Markers and General Health in Subjects with Overweight or Prehypertension/Mild Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 11
Issue 8
10.3390/nu11081823
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

Choline: Exploring the Growing Science on Its Benefits for Moms and Babies

by
Hunter W. Korsmo
1,2,
Xinyin Jiang
1,2,* and
Marie A. Caudill
3,*
1
Program in Biochemistry, Graduate Center of the City University of New York, New York, NY 10016, USA
2
Department of Health and Nutrition Sciences, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA
3
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
*
Authors to whom correspondence should be addressed.
Nutrients 2019, 11(8), 1823; https://doi.org/10.3390/nu11081823
Submission received: 2 July 2019 / Revised: 1 August 2019 / Accepted: 5 August 2019 / Published: 7 August 2019
(This article belongs to the Special Issue Choline as an Essential Nutrient—Metabolism, Requirements throughout Lifespan and Clinical Impact)
Browse Figures
Versions Notes

Abstract

:
The importance of ensuring adequate choline intakes during pregnancy is increasingly recognized. Choline is critical for a number of physiological processes during the prenatal period with roles in membrane biosynthesis and tissue expansion, neurotransmission and brain development, and methyl group donation and gene expression. Studies in animals and humans have shown that supplementing the maternal diet with additional choline improves several pregnancy outcomes and protects against certain neural and metabolic insults. Most pregnant women in the U.S. are not achieving choline intake recommendations of 450 mg/day and would likely benefit from boosting their choline intakes through dietary and/or supplemental approaches.

1. Introduction

The importance of ensuring adequate choline intakes during pregnancy is increasingly recognized. The American Medical Association (AMA) in 2017 published new advice stating that prenatal vitamin supplements should contain ‘evidence-based’ amounts of choline [1]. Similarly, in 2018, the American Academy of Pediatrics recognized choline as a ‘brain-building’ nutrient and called upon pediatricians to ensure pregnant women and young children have adequate intakes of choline [2].
Choline, like vitamin D and docosahexaenoic acid (DHA), can be synthesized in the body but not in amounts sufficient to meet metabolic demands. In 1998, choline was recognized as an essential nutrient by the Institute of Medicine (now National Academy of Medicine) when it established dietary recommendations in the form of adequate intakes [3]. The choline adequate intake (AI) level is 425 mg choline/day for women of reproductive age with upward adjustments to 450 mg choline/day during pregnancy and 550 mg choline/day during lactation [3]. Although widely distributed in the diet, choline is absent from most prenatal vitamins currently on the market, and less than ten percent of pregnant women achieve target intake levels [4].

2. Food Sources of Choline

Choline is found in both animal and plant source foods; however, animal source foods typically contain more choline per gram of food product. Beef, eggs, chicken, fish, and pork are concentrated sources of choline providing more than 60 mg per 100 g [5]. Among plant source foods, nuts, legumes, and cruciferous vegetables (e.g., broccoli) are relatively good sources providing at least 25 mg per 100 g [5]. Although not a concentrated source, cow’s milk is a main contributor to dietary choline intake in the U.S. [6].
Various forms of choline are found in food. The most prominent dietary form of choline is usually phosphatidylcholine (PC) with smaller amounts of free choline, phosphocholine, sphingomyelin, glycerophosphocholine, and lysophosphatidylcholine (LPC) [5]. All of these choline forms are interchangeable within the body and contribute to an individual’s “total” choline intake. Although betaine is a choline derivative, it is not considered a dietary source of choline because there is no direct route for converting betaine to choline. However, dietary betaine may have a choline-sparing effect since it participates in the remethylation of homocysteine, thus reducing the need for endogenous choline oxidation to betaine [7] and lowering the dietary requirement for choline. Upon absorption of choline, water-soluble biomolecules (free choline, phosphocholine and glycerophosphocholine) enter portal blood, while lipid-soluble forms (PC, LPC and sphingomyelin) are incorporated into chylomicrons [8].

3. Choline Function

Within the body, choline is critical for a number of functions with wide-ranging roles in metabolic and physiologic processes. The choline derivative, PC, is a major constituent of all cell membranes and is required for the biosynthesis of lipoproteins, including very low-density lipoproteins (VLDLs), which facilitate the hepatic export of lipid (Figure 1). Inadequate choline intake disturbs the integrity of cellular membranes resulting in ‘leaky membranes’ [9] and impairs the mobilization of fat from liver resulting in fatty liver [10]. Acetylcholine functions as a neurotransmitter in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas [11]. In the PNS, acetylcholine activates skeletal muscle and is a major neurotransmitter in the autonomic nervous system [12]. Sphingomyelin is a constituent of the myelin sheath [13], which covers the axons of nerve cells and facilitates efficient transmission of nerve signals. Finally, betaine is a source of methyl groups for S-adenosylmethionine (SAM)-dependent methyltransferases and for folate mediated one-carbon metabolism following the demethylation of dimethylglycine (produced when betaine is used as a methyl donor) within the mitochondria of hepatocytes [8].

4. Choline Metabolism.

Choline metabolism to its various biomolecules occurs mostly in the liver (Figure 1), with the exception of acetylcholine generation, which occurs in both cholinergic neurons and the placenta [14]. In liver (and other nucleated cells), free choline is initially partitioned to the cytidine diphosphate (CDP)-choline pathway (also known as the Kennedy pathway) for the generation of PC, a phospholipid that can further contribute its phosphocholine headgroup to ceramide for the synthesis of sphingomyelin. Alternatively, free choline can be oxidized to betaine in a two-step irreversible reaction catalyzed by choline dehydrogenase (CHDH) and betaine aldehyde dehydrogenase. The oxidation of choline to betaine has been referred to as a ‘spillover’ pathway [15] that is most active under conditions of surplus choline. Betaine participates in the remethylation of homocysteine to methionine by betaine-homocysteine S-methyltransferase (BHMT). Methionine can subsequently be converted to SAM, the universal methyl donor for over 100 cellular methylation reactions including the phosphatidylethanolamine N-methyltransferase (PEMT) pathway.
The PEMT pathway facilitates de novo choline biosynthesis whereby phosphatidylethanolamine (PE), a non-choline containing phospholipid, undergoes sequential methylation to PC using SAM as the methyl donor (Figure 1). Primary sources of the methyl groups used for SAM-dependent methylation of PE include methionine, methyl-folate, and choline itself following its oxidation to betaine. Indeed, tracer studies in pregnant women have demonstrated substantial use of choline-derived methyl groups for the synthesis of PC via the PEMT pathway [16]. An explanation for this apparent inefficiency may stem from differences in the fatty acid composition of the PC molecules derived from the PEMT pathway as opposed to the CDP-choline pathway. PEMT derived PC molecules are enriched in long-chain polyunsaturated fatty acids (PUFAs) (C18–C22), whereas CDP-PC molecules are enriched in saturated fatty acids (C16, C18) [17]. Both PEMT and CDP-choline derived PC molecules can be incorporated into VLDL and exported from liver to circulation for uptake by other tissues including the placenta (Figure 1).
During the third trimester of pregnancy, the activities of the CDP-choline and PEMT pathways are upregulated; however, only the PC products derived from the PEMT pathway are enriched in cord plasma [16], demonstrating preferential transport of PEMT derived PC to the developing fetus. This preferential shuttling of PEMT-derived PCs during the third trimester may be due to its enrichment in DHA (22:6n3), a polyunsaturated omega 3 fatty acid that accumulates in the neonatal brain during the third trimester of pregnancy [18]. Notably, studies in women of reproductive age have shown that choline supplementation upregulates the PEMT pathway [16] and results in greater enrichment of PC-DHA in circulating red blood cells [19], suggesting that choline supplementation may be a strategy for improving the bioavailability of DHA.
In addition to PC-DHA, LPC-DHA, a hydrolytic product of PEMT-PC, may represent another source of DHA for the developing fetus [20]. LPC-DHA circulates bound to albumin and can be taken up by the placenta via the major facilitator superfamily domain 2 protein (MFSD2A), an LPC symporter with high affinity for LPC-DHA [21,22]. Genetic loss of MFSD2A expression in mice results in impaired accretion of DHA in the fetal brain and eye, suggesting that LPC-DHA is a critical form of DHA for transport across the placenta, the fetal blood-brain barrier and/or the retinal epithelium [23].
The metabolism of choline is influenced by single nucleotide polymorphisms (SNPs) found in genes that encode enzymes in folate and choline dependent pathways [24]. For example, loss-of-function variants in folate metabolizing enzymes (e.g., methylenetetrahydrofolate reductase [MTHFR], 5-methyltetrahydrofolate-homocysteine methyltransferase [MTR], and methylenetetrahydrofolate dehydrogenase 1 [MTHFD1]) strain cellular PC production, possibly via impaired folate-dependent PEMT-PC biosynthesis, even when the choline AI is consumed [25]. Similarly, disturbances in the metabolic partitioning of choline have been observed at levels of choline intake approximating the choline AI among women harboring SNPs within choline metabolizing enzymes (PEMT, CHDH, BHMT, and choline kinase alpha [CHKA]) [26]. Some of these SNPs have also been shown to influence the risk of developing organ dysfunction, a manifestation of choline deficiency, when dietary choline intake is restricted [27]. Overall these “risk” genotypes would be expected to increase the dietary requirement for choline.

5. Choline and Fetal Development

During fetal development, large amounts of choline-derived phospholipids, such as phosphatidylcholine and sphingomyelin, are needed to support rapid cell division, growth, and myelination. The choline derived neurotransmitter acetylcholine influences many processes in the developing brain (e.g., progenitor cell proliferation and differentiation, neurogenesis, gliogenesis, cell survival, morphology and migration, and synaptic plasticity) [28,29], and supports normal development of the hippocampus [30], a region of the brain with roles in learning, memory, and attention. As a major source of methyl groups, choline also facilitates methylation of cytosine residues within promoter regions of the placental and fetal genome, an epigenetic modification that influences gene expression and can have lasting effects on metabolic and physiologic processes [31].

6. Choline and Pregnancy Outcomes

Choline intake during pregnancy has been shown to influence numerous metabolic and physiologic processes as outlined below and highlighted in Figure 2.

6.1. Epigenetic Programming of Postnatal Health

As a methyl donor, choline influences DNA and histone methylation – two central epigenomic processes that regulate gene expression [31]. During murine pregnancy, maternal choline deficiency has been shown to modulate the epigenome of the offspring, with lasting adverse effects on functions related to fetal growth [32] as well as brain development and angiogenesis [33,34]. Rodent studies have also demonstrated modulatory effects of maternal choline supplementation during pregnancy on the placental and fetal epigenome [35,36,37], with some reports of reduced disease risk [36,37]. In humans, gestational choline may influence offspring stress reactivity. Consumption of a higher maternal choline intake (930 vs. 480 mg choline/day) throughout the third trimester of pregnancy increased promoter region methylation of the placental corticotropin-releasing hormone (CRH) gene and decreased its expression (Table 1) [38]. CRH is a regulatory protein in the hypothalamus-pituitary-adrenal (HPA) axis that mediates stress reactivity by stimulating cortisol production by the adrenal gland. Like the brain, the placenta makes CRH, which can subsequently enter fetal circulation and activate the HPA axis [39]. As expected, this same study found lower cord blood cortisol concentrations in the newborns of mothers consuming 930 vs. 480 mg choline/day. Because a heightened response to stress increases the risk of depression, hypertension, type 2 diabetes mellitus, and immunological disorders later in life [40,41], the children with decreased stress-reactivity at birth may be less likely to develop mental and cardio-metabolic diseases [42].

6.2. Placental Function

The placenta is a critical organ of pregnancy that mediates nutrient and oxygen supply to the developing fetus. Proper functioning of the placenta depends on development of a vasculature that enables sufficient blood flow to the developing fetus. Inadequate vascularization of the placenta can lead to pregnancy disorders characterized by impaired fetal growth such as intrauterine growth restriction (IUGR) and preeclampsia [57]. Emerging data from a growing number of studies suggest that choline supply can beneficially influence functional processes of the placenta, including angiogenesis [50,58,59], inflammation [58,59,60], and macronutrient transport [61]. Based on rodent data, prenatal choline may also be a nutritional approach to mitigate placental insufficiency [60,62]. In the Dlx3 ± mouse model of placental insufficiency, gestational choline improved early fetal growth [62], possibly by increasing the size of the placental labyrinth [60], a region of the placenta that contains the villi where nutrients pass from the maternal blood into the fetal blood.
In humans, consumption of additional choline (930 vs. 480 mg choline/day) during the third trimester of pregnancy reduced the production of placental soluble fms-like tyrosine kinase 1 (sFlt1) [50] (Table 1), an anti-angiogenic protein that sequesters vascular endothelial growth factor (VEGF) in maternal circulation and contributes to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Downregulation of placental sFLT1 production by high choline was also demonstrated in an in-vitro follow-up study using human trophoblast cells [58], an effect that appeared to be mediated through attenuation of the protein kinase C (PKC) signaling pathway.

6.3. Macronutrient Metabolism and Energy Homeostasis

Several studies have demonstrated an interaction between choline and macronutrient metabolism during pregnancy [63,64,65]. In a mouse model of high-fat feeding-induced gestational diabetes mellitus (GDM), Nam et al. [63] found that maternal choline supplementation prevented fetal overgrowth during mid-gestation, the most common complication of GDM. This effect was associated with a dampening of the mechanistic target of rapamycin (mTOR) signaling pathway in the placenta, which promotes placental transport of glucose and fat [63,66,67]. A follow-up study at a later gestational time point reported that maternal choline supplementation normalized whole-body adiposity and reduced hepatic triglyceride accumulation possibly by downregulating lipogenic gene expression in the GDM mouse embryos [64]. In addition, an examination of the placental structure suggested that choline supplementation mitigated the increase in both placental junctional zone thickness and number of glycogen cells in GDM rodent placentas [65]. Betaine supplementation of GDM mice showed similar, but not identical, phenotypic outcomes suggesting that the beneficial effects of choline supplementation on GDM fetal metabolism may be partially mediated via its oxidation to betaine [68]. While the long-term outcome of maternal choline supplementation on GDM offspring metabolism remains to be determined, methyl donor supplementation during murine pregnancy has been shown to block some of the adverse effects of maternal high fat feeding on offspring physiology possibly by reversing diet-induced global hypomethylation within the offspring CNS [69].

6.4. Neurodevelopment and Cognitive Function

Studies in rodents have consistently shown that high choline intake during gestation improves cognitive function in adulthood and prevents the memory decline associated with old age [70,71,72]. Likewise, many studies have shown that choline inadequacy during gestation adversely influences offspring brain development and function [33,34,73,74,75,76]. For example, piglets born to choline-deficient mothers had lower brain weight, volume, and less white and grey matter at 30 days of age as compared to control piglets [73,74,75]. A recent study reported that low choline during gestation also disrupted retinal development and visual function in mice [77]. Possible mechanisms by which maternal choline influences offspring neurodevelopment and cognitive function are related to (i) the use of choline for phospholipid membrane synthesis; (ii) facilitation of DHA uptake [21]; (iii) myelination of neurons during early development [13,78]; (iv) alterations in hippocampal acetylcholine metabolism [28,79]; (v) modulation of neurogenesis and neuronal differentiation [76,77]; and (vi) modifications on epigenetic marks that govern hippocampal angiogenesis and cellular proliferation [33,34]. All of these choline-induced outcomes ultimately influence cellular proliferation, differentiation, morphology, dendritic branching, neurogenesis, and potentiation of the offspring hippocampus [76,80,81,82].
A few prospective observational studies have explored the relationship between maternal choline status (intake or blood levels) during human pregnancy and cognitive development in children (Table 1). Wu et al. found that concentrations of maternal plasma choline and betaine at 16 weeks of gestation were positively associated with infant cognitive test scores at 18 months [46]. The Project Viva study observed an association of better visual memory among 7-year-old children of mothers with choline intakes in the top versus the bottom quartile during the second trimester of pregnancy [49]. Most recently, higher serum choline concentrations in mothers with infections at gestational week 16 were associated with better inhibition of auditory cerebral response in newborns and improved development of self-regulation in 1-year old infants [55].
Findings from randomized clinical trials (RCTs) in support of a beneficial effect of prenatal choline on cognitive outcomes are also beginning to emerge (Table 1). In a randomized controlled feeding study, faster processing speed was observed among infants born to mothers consuming 930 versus 480 mg choline/day during their third trimester of pregnancy [53]. Moreover, children whose mothers consumed 930 (versus 480) mg choline/day performed significantly better on a task of color-location memory at age 7 years, suggesting a long-term beneficial effect of prenatal choline supplementation on offspring cognition [56]. Another RCT reported improved cerebral inhibition, an indicator of attention, among offspring at 5 weeks of age [51], and reduced attentional problems and social withdrawal at 40 months of age [52] with choline supplementation given from the second trimester of pregnancy, and then postnatally to the infant.
However, not all studies have found a relationship between maternal choline status/intake and indicators of offspring cognition, which may indicate (among other things) that not all aspects of cognition are choline-responsive. Signore et al. [44] found no associations between cord blood choline concentrations and intellectual quotient (IQ) scores in children at 5 years of age, while Villamor et al. [47] reported no associations between maternal choline intake and vocabulary or visual-motor scores in children at 3 years of age. In addition, an RCT [48] that randomized women to supplemental choline (750 mg/day) or placebo from 18 weeks gestation through 90 days postpartum reported no benefit of maternal choline supplementation on infant cognition as assessed using a variety of cognitive domains including general cognitive function, language development, and episodic and visuospatial memory.

6.5. Protection from Neural Insults

In addition to improving some aspects of offspring cognition, findings from animal studies show that perinatal choline protects the brain from the neuropathological changes associated with Alzheimer’s disease (AD) [83,84], fetal alcohol syndrome [85,86,87], autism [88,89], Down syndrome [90,91,92,93], and early-life iron deficiency [94,95]. In the Ts65DN mouse model of Down syndrome, maternal choline supplementation improved spatial memory and hippocampal neurogenesis in the brains of the Ts65Dn offspring [90]. Notably, mechanistic studies in which a choline tracer was administered to the adult Ts65DN offspring indicated that prenatal choline permanently upregulated PEMT activity and the delivery of PEMT derived PC (enriched in DHA) to the brains of these mice [93]. Maternal choline supplementation also normalized the number and density of cholinergic neurons in the medial septum [92]. Since the loss of cholinergic neurons is often seen in AD, studies on the trisomy mice highlight the potential of maternal choline supplementation as a preventative measure for early-onset AD [96]. Indeed, in the APP/PS1 mouse model of AD, perinatal choline supplementation reduced the number and total area of amyloid plaque [83]. Interestingly, cross-generational effects of perinatal choline have been observed with fewer cognitive deficits in the F2 generation of APP/PS1 mice born to F1 mice that were not supplemented with additional choline during pregnancy themselves [84]. Prenatal choline supplementation also mitigated long-term neurobehavioral abnormalities and transcriptomic alterations in gene networks associated with autism and schizophrenia in rat offspring exposed to fetal-neonatal iron deficiency [94,95].
Although few human studies have explored the effects of maternal choline supplementation on cognitive deficits arising from neural insults, preliminary data from a recent study found that this intervention mitigated some of the adverse effects of prenatal alcohol exposure on infant growth and cognitive function (Table 1) [54]. These beneficial effects of prenatal choline in fetal alcohol exposure echoed the data from alcohol-exposed animals and could be related to choline’s role as a methyl donor and its ability to counter epigenetic changes that occur in various brain regions as a consequence of prenatal alcohol exposure [97,98]. Prenatal choline may also protect against the development of congenital malformations of the central nervous system, commonly referred to as neural tube defects (NTDs). For example, both maternal choline intake and biomarkers of choline status during pregnancy have been inversely associated with offspring NTD risk [43,45].

7. Choline Requirements during Pregnancy

The endogenous synthesis of choline via the PEMT pathway is elevated during the second half of pregnancy due to increases in estrogen and upregulation of the PEMT gene, which contains estrogen response elements within its promoter region [99]. However, as previously mentioned, the upregulation of the PEMT pathway increases the demand for methyl groups from various sources including choline itself [16]. Indeed, data from human feeding studies suggest that the choline adequate intake (AI) of 450 mg/day may not be sufficient in meeting the demands of pregnancy. For example, pregnant women consuming 480 mg choline/day exhibit 40–60% lower circulating concentrations of the choline-derived methyl metabolites, betaine, dimethylglycine, and sarcosine as compared to nonpregnant women consuming this same level of choline intake [100]. The partitioning of choline towards betaine (versus the CDP-choline pathway) is also diminished among pregnant (versus nonpregnant) women with choline intakes of 480 mg/day, despite greater use of betaine as a methyl donor in the pregnant state [16]. Notably, a doubling of choline intake during pregnancy (i.e., 930 versus 480 mg choline/day) restores the partitioning of choline between the oxidative and CDP-choline pathways to that of a nonpregnant state [16]; it also increases circulating concentrations of choline-derived methyl metabolites [100], increases placental DNA methylation [38], and overcomes some of the metabolic inefficiencies caused by common polymorphisms in folate and choline metabolizing genes [25,26]. Moreover, this higher level of choline intake beneficially influenced several pregnancy outcomes including improvements in indicators of neonatal stress reactivity [38], reductions in placental sFLT1 production [50], faster information processing speed among infants [53], and better memory in children at age 7 years [56].

8. Safety

The tolerable upper intake level (UL) of choline is 3.5 g/day for adults and was established to prevent hypotension and fishy body odor [3]. To date, none of the RCTs conducted in healthy pregnant women have reported any adverse effects of choline supplementation at levels ranging from 550–900 mg/day [48,51,100]. However, a few animal studies have reported that supplementing the maternal diet with very high levels of methyl nutrients (with choline as one of the components) increased susceptibility to colitis [101] and asthma-like allergic airway disease [102], as well as impaired energy homeostasis when combined with prenatal protein restriction [103]. In addition, choline can be converted to trimethylamine N-oxide (TMAO), a risk indicator of cardio-metabolic diseases, via the action of gut microbes. However, whether TMAO has a causative role in human chronic disease development is unknown [104,105], and the long-term influence of choline intake on maternal and offspring TMAO status and health requires further investigation. In summary, certain aspects of fetal development may follow a U-shaped response pattern to choline supply (and other methyl donors), whereby both low and excessively high exposures could adversely influence offspring health.

9. Conclusions and Future Directions

Data from both animal and human studies highlight the importance of ensuring an adequate choline intake during pregnancy. Supplementing the maternal diet with additional choline has been shown to improve offspring cognition, neurodevelopment, and placental functioning, and to protect against neural and metabolic insults. However, RCTs on prenatal choline and pregnancy outcomes are limited and the dose–response relationship between maternal choline intake and offspring health remains to be fully discerned. Future clinical interventions with larger sample sizes, multiple dosages, specific endpoints with clinical utility, mechanistic measurements, and long-term follow-up are needed to establish maternal choline intake recommendations that optimize fetal development and reduce the risk of pregnancy complications. In the interim, consumption of 450–1000 mg choline/day appears to be an intake level that would support fetal development and improve pregnancy outcomes based on the available and emerging science.

Author Contributions

Conceptualization, H.W.K., M.A.C. and X.J.; writing—original draft preparation, H.W.K., M.A.C. and X.J.; writing—review and editing, M.A.C.

Funding

This research was funded in part by the National Institute of Food and Agriculture, U.S. Department of Agriculture, Hatch project, under accession number 1013729 (M.A.C.); the National Institute of General Medical Sciences (NIGMS) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 1SC2DK108292 (X.J.); and the NIGMS, 1SC3GM132010 (X.J.)

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. AMA Wire. AMA Backs Global Health Experts in Calling Infertility a Disease. Available online: https://wire.ama-assn.org/ama-news/ama-backs-global-health-experts-calling-infertility-disease (accessed on 10 June 2019).
  2. Schwarzenberg, S.J.; Georgieff, M.K.; Committee on Nutrition. Advocacy for Improving Nutrition in the First 1000 Days to Support Childhood Development and Adult Health. Pediatrics 2018, 141, e20173716. [Google Scholar] [CrossRef] [PubMed]
  3. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline; National Academy Press: Washington, DC, USA, 1998. [Google Scholar]
  4. Wallace, T.C.; Fulgoni, V.L. Usual Choline Intakes Are Associated with Egg and Protein Food Consumption in the United States. Nutrients 2017, 9, 839. [Google Scholar] [CrossRef] [PubMed]
  5. Patterson, Y.; Bhagwat, A.; Williams, R.; Howe, C.; Holden, M. USDA Database for The Choline Content of Common Foods; Release 2; Agricultural Research Service: Washington, DC, USA, 2008.
  6. Chester, D.; Goldman, J.; Ahuja, J.; Moshfegh, A. Dietary Intakes of Choline: What We Eat in America, NHANES 2007-Food Surveys Research Group Dietary Data Brief No. October 2011. Available online: http://ars.usda.gov/Services/docs.htm?docid=19476 (accessed on 10 June 2019).
  7. Dilger, R.N.; Garrow, T.A.; Baker, D.H. Betaine can partially spare choline in chicks but only when added to diets containing a minimal level of choline. J. Nutr. 2007, 137, 2224–2228. [Google Scholar] [CrossRef] [PubMed]
  8. Klatt, K.; Caudill, M. Folate, Choline, Vitamin B12 and Vitamin B6. In Biochemical, Physiological, & Molecular Aspects of Human Nutrition, 4th ed.; Stipanuk, M., Caudill, M., Eds.; Elsevier Saunders: St Louis, MO, USA, 2018. [Google Scholar]
  9. Li, Z.; Agellon, L.B.; Allen, T.M.; Umeda, M.; Jewell, L.; Mason, A.; Vance, D.E. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab. 2006, 3, 321–331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Zeisel, S.H.; Klatt, K.C.; Caudill, M.A. Choline. Adv. Nutr. 2018, 9, 58–60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Ballinger, E.C.; Ananth, M.; Talmage, D.A.; Role, L.W. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron 2016, 91, 1199–1218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. McCorry, L.K. Physiology of the Autonomic Nervous System. Am. J. Pharm. Educ. 2007, 71, 78. [Google Scholar] [CrossRef] [PubMed]
  13. Morell, P.; Quarles, R. Characteristic Composition of Myelin. In Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th ed.; Siegel, G.J., Agranoff, B.W., Albers, R.W., Fisher, S.K., Uhler, M.D., Eds.; Lippincott-Raven: Philadelphia, PA, USA, 1999. [Google Scholar]
  14. Kwan, S.; King, J.; Caudill, M. Choline and Placental Trophoblast Development. In Human Placental Trophoblasts; Duttaroy, A., Basak, S., Eds.; CRC Press, Taylor & Francis Group: Boca Raton, FL, USA, 2015. [Google Scholar]
  15. Park, E.I.; Garrow, T.A. Interaction between Dietary Methionine and Methyl Donor Intake on Rat Liver Betaine-homocysteine Methyltransferase Gene Expression and Organization of the Human Gene. J. Biol. Chem. 1999, 274, 7816–7824. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Yan, J.; Jiang, X.; West, A.A.; Perry, C.A.; Malysheva, O.V.; Brenna, J.T.; Stabler, S.P.; Allen, R.H.; Gregory, J.F., 3rd; Caudill, M.A. Pregnancy alters choline dynamics: Results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women. Am. J. Clin. Nutr. 2013, 98, 1459–1467. [Google Scholar] [CrossRef]
  17. Delong, C.J.; Shen, Y.-J.; Thomas, M.J.; Cui, Z. Molecular Distinction of Phosphatidylcholine Synthesis between the CDP-Choline Pathway and Phosphatidylethanolamine Methylation Pathway. J. Biol. Chem. 1999, 274, 29683–29688. [Google Scholar] [CrossRef] [Green Version]
  18. Clandinin, M.; Chappell, J.; Leong, S.; Heim, T.; Swyer, P.; Chance, G. Intrauterine fatty acid accretion rates in human brain: Implications for fatty acid requirements. Early Hum. Dev. 1980, 4, 121–129. [Google Scholar] [CrossRef]
  19. A West, A.; Yan, J.; Jiang, X.; A Perry, C.; Innis, S.M.; A Caudill, M. Choline intake influences phosphatidylcholine DHA enrichment in nonpregnant women but not in pregnant women in the third trimester. Am. J. Clin. Nutr. 2013, 97, 718–727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Lagarde, M.; Bernoud, N.; Brossard, N.; Lemaitre-Delaunay, D.; Thies, F.; Croset, M.; Lecerf, J. Lysophosphatidylcholine as a Preferred Carrier Form of Docosahexaenoic Acid to the Brain. J. Mol. Neurosci. 2001, 16, 201–204; discussion 215–221. [Google Scholar] [CrossRef]
  21. Nguyen, L.N.; Ma, D.; Shui, G.; Wong, P.; Cazenave-Gassiot, A.; Zhang, X.; Wenk, M.R.; Goh, E.L.K.; Silver, D.L. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 2014, 509, 503–506. [Google Scholar] [CrossRef] [PubMed]
  22. Ferchaud-Roucher, V.; Kramer, A.; Silva, E.; Pantham, P.; Weintraub, S.T.; Jansson, T.; Powell, T.L. A potential role for lysophosphatidylcholine in the delivery of long chain polyunsaturated fatty acids to the fetal circulation. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 394–402. [Google Scholar] [CrossRef] [PubMed]
  23. Wong, B.H.; Chan, J.P.; Cazenave-Gassiot, A.; Poh, R.W.; Foo, J.C.; Galam, D.L.; Ghosh, S.; Nguyen, L.N.; Barathi, V.A.; Yeo, S.W.; et al. Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development. J. Biol. Chem. 2016, 291, 10501–10514. [Google Scholar] [CrossRef] [PubMed]
  24. Ganz, A.B.; Klatt, K.C.; Caudill, M.A. Common Genetic Variants Alter Metabolism and Influence Dietary Choline Requirements. Nutrients 2017, 9, 837. [Google Scholar] [CrossRef] [PubMed]
  25. Ganz, A.B.; Shields, K.; Fomin, V.G.; Lopez, Y.S.; Mohan, S.; Lovesky, J.; Chuang, J.C.; Ganti, A.; Carrier, B.; Yan, J.; et al. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. FASEB J. 2016, 30, 3321–3333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ganz, A.B.; Cohen, V.V.; Swersky, C.C.; Stover, J.; Vitiello, G.A.; Lovesky, J.; Chuang, J.C.; Shields, K.; Fomin, V.G.; Lopez, Y.S.; et al. Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations. Int. J. Mol. Sci. 2017, 18, 252. [Google Scholar] [CrossRef] [PubMed]
  27. Da Costa, K.-A.; Kozyreva, O.G.; Song, J.; Galanko, J.A.; Fischer, L.M.; Zeisel, S.H. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. 2006, 20, 1336–1344. [Google Scholar] [CrossRef] [PubMed]
  28. Abreu-Villaça, Y.; Filgueiras, C.C.; Manhães, A.C. Developmental aspects of the cholinergic system. Behav. Brain Res. 2011, 221, 367–378. [Google Scholar] [CrossRef] [PubMed]
  29. Lauder, J.M.; Schambra, U.B. Morphogenetic Roles of Acetylcholine. Environ. Heal. Perspect. 1999, 107 (Suppl. 1), 65–69. [Google Scholar]
  30. Blusztajn, J.K.; Rinnofner, J. Intrinsic Cholinergic Neurons in the Hippocampus: Fact or Artifact? Front. Synaptic Neurosci. 2016, 8, 6. [Google Scholar] [CrossRef] [PubMed]
  31. Blusztajn, J.K.; Mellott, T.J. Choline nutrition programs brain development via DNA and histone methylation. Central Nerv. Syst. Agents Med. Chem. 2012, 12, 82–94. [Google Scholar] [CrossRef]
  32. Kovacheva, V.P.; Mellott, T.J.; Davison, J.M.; Wagner, N.; Lopez-Coviella, I.; Schnitzler, A.C.; Blusztajn, J.K. Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation ofDnmt1Expression. J. Biol. Chem. 2007, 282, 31777–31788. [Google Scholar] [CrossRef] [PubMed]
  33. Mehedint, M.G.; Craciunescu, C.N.; Zeisel, S.H. Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus. Proc. Natl. Acad. Sci. USA 2010, 107, 12834–12839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Mehedint, M.G.; Niculescu, M.D.; Craciunescu, C.N.; Zeisel, S.H. Choline deficiency alters global histone methylation and epigenetic marking at the Re1 site of the calbindin 1 gene. FASEB J. 2010, 24, 184–195. [Google Scholar] [CrossRef]
  35. Kwan, S.T.C.; King, J.H.; Grenier, J.K.; Yan, J.; Jiang, X.; Roberson, M.S.; Caudill, M.A. Maternal Choline Supplementation during Normal Murine Pregnancy Alters the Placental Epigenome: Results of an Exploratory Study. Nutrients 2018, 10, 417. [Google Scholar] [CrossRef]
  36. Medici, V.; Shibata, N.M.; Kharbanda, K.K.; Islam, M.S.; Keen, C.L.; Kim, K.; Tillman, B.; French, S.W.; Halsted, C.H.; LaSalle, J.M. Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics 2014, 9, 286–296. [Google Scholar] [CrossRef]
  37. Kovacheva, V.P.; Davison, J.M.; Mellott, T.J.; Rogers, A.E.; Yang, S.; O’Brien, M.J.; Blusztajn, J.K. Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival. FASEB J. 2009, 23, 1054–1063. [Google Scholar] [CrossRef]
  38. Jiang, X.; Yan, J.; West, A.A.; Perry, C.A.; Malysheva, O.V.; Devapatla, S.; Pressman, E.; Vermeylen, F.; Caudill, M.A. Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J. 2012, 26, 3563–3574. [Google Scholar] [CrossRef] [PubMed]
  39. Majzoub, J.A.; Karalis, K.P. Placental corticotropin-releasing hormone: Function and regulation. Am. J. Obstet. Gynecol. 1999, 180, S242–S246. [Google Scholar] [CrossRef]
  40. Levitt, N.S.; Lambert, E.V.; Woods, D.; Hales, C.N.; Andrew, R.; Seckl, J.R. Impaired Glucose Tolerance and Elevated Blood Pressure in Low Birth Weight, Nonobese, Young South African Adults: Early Programming of Cortisol Axis. J. Clin. Endocrinol. Metab. 2000, 85, 4611–4618. [Google Scholar] [PubMed]
  41. Xiong, F.; Zhang, L. Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease. Front. Neuroendocrinol. 2013, 34, 27–46. [Google Scholar] [CrossRef] [PubMed]
  42. Chen, M.; Zhang, L. Epigenetic mechanisms in developmental programming of adult disease. Drug Discov. Today 2011, 16, 1007–1018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Shaw, G.M.; Carmichael, S.L.; Yang, W.; Selvin, S.; Schaffer, D.M. Periconceptional Dietary Intake of Choline and Betaine and Neural Tube Defects in Offspring. Am. J. Epidemiol. 2004, 160, 102–109. [Google Scholar] [CrossRef] [Green Version]
  44. Signore, C.; Ueland, P.M.; Troendle, J.; Mills, J.L. Choline concentrations in human maternal and cord blood and intelligence at 5 y of age. Am. J. Clin. Nutr. 2008, 87, 896–902. [Google Scholar] [CrossRef] [Green Version]
  45. Shaw, G.M.; Finnell, R.H.; Blom, H.J.; Carmichael, S.L.; Vollset, S.E.; Yang, W.; Ueland, P.M. Choline and Risk of Neural Tube Defects in a Folate-fortified Population. Epidemiology 2009, 20, 714–719. [Google Scholar] [CrossRef] [Green Version]
  46. Wu, B.T.; Dyer, R.A.; King, D.J.; Richardson, K.J.; Innis, S.M. Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants. PLoS ONE 2012, 7, e43448. [Google Scholar] [CrossRef]
  47. Villamor, E.; Rifas-Shiman, S.L.; Gillman, M.W.; Oken, E. Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr. Périnat. Epidemiol. 2012, 26, 328–335. [Google Scholar] [CrossRef]
  48. Cheatham, C.L.; Goldman, B.D.; Fischer, L.M.; Da Costa, K.-A.; Reznick, J.S.; Zeisel, S.H. Phosphatidylcholine supplementation in pregnant women consuming moderate-choline diets does not enhance infant cognitive function: A randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr. 2012, 96, 1465–1472. [Google Scholar] [CrossRef] [PubMed]
  49. Boeke, C.E.; Gillman, M.W.; Hughes, M.D.; Rifas-Shiman, S.L.; Villamor, E.; Oken, E. Choline intake during pregnancy and child cognition at age 7 years. Am. J. Epidemiol. 2013, 177, 1338–1347. [Google Scholar] [CrossRef] [PubMed]
  50. Jiang, X.; Bar, H.Y.; Yan, J.; Jones, S.; Brannon, P.M.; West, A.A.; Perry, C.A.; Ganti, A.; Pressman, E.; Devapatla, S.; et al. A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1). FASEB J. 2013, 27, 1245–1253. [Google Scholar] [CrossRef] [PubMed]
  51. Ross, R.G.; Hunter, S.K.; McCarthy, L.; Beuler, J.; Hutchison, A.K.; Wagner, B.D.; Leonard, S.; Stevens, K.E.; Freedman, R. Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. Am. J. Psychiatry 2013, 170, 290–298. [Google Scholar] [CrossRef] [PubMed]
  52. Ross, R.G.; Hunter, S.K.; Hoffman, M.C.; McCarthy, L.; Chambers, B.M.; Law, A.J.; Leonard, S.; Zerbe, G.O.; Freedman, R. Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. Am. J. Psychiatry 2016, 173, 509–516. [Google Scholar] [CrossRef] [PubMed]
  53. Caudill, M.A.; Strupp, B.J.; Muscalu, L.; Nevins, J.E.H.; Canfield, R.L. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: A randomized, double-blind, controlled feeding study. FASEB J. 2018, 32, 2172–2180. [Google Scholar] [CrossRef] [PubMed]
  54. Jacobson, S.W.; Carter, R.C.; Molteno, C.D.; Stanton, M.E.; Herbert, J.S.; Lindinger, N.M.; Lewis, C.E.; Dodge, N.C.; Hoyme, H.E.; Zeisel, S.H.; et al. Efficacy of Maternal Choline Supplementation During Pregnancy in Mitigating Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Alcohol Clin. Exp. Res. 2018, 42, 1327–1341. [Google Scholar] [CrossRef]
  55. Freedman, R.; Hunter, S.K.; Law, A.J.; Wagner, B.D.; D’Alessandro, A.; Christians, U.; Noonan, K.; Wyrwa, A.; Hoffman, M.C. Higher Gestational Choline Levels in Maternal Infection Are Protective for Infant Brain Development. J. Pediatr. 2019, 208, 198–206.e2. [Google Scholar] [CrossRef]
  56. Bahnfleth, C.; Canfield, R.; Nevins, J.; Caudill, M.; Strupp, B. Prenatal Choline Supplementation Improves Child Color-location Memory Task Performance at 7 Y of Age (FS05-01-19). Curr. Dev. Nutr. 2019, 3 (Suppl. 1). [Google Scholar] [CrossRef]
  57. Pereira, R.D.; De Long, N.E.; Wang, R.C.; Yazdi, F.T.; Holloway, A.C.; Raha, S. Angiogenesis in the Placenta: The Role of Reactive Oxygen Species Signaling. BioMed Res. Int. 2015, 2015, 814543. [Google Scholar] [CrossRef]
  58. Jiang, X.; Jones, S.; Andrew, B.Y.; Ganti, A.; Malysheva, O.V.; Giallourou, N.; Brannon, P.M.; Roberson, M.S.; Caudill, M.A. Choline Inadequacy Impairs Trophoblast Function and Vascularization in Cultured Human Placental Trophoblasts. J. Cell. Physiol. 2014, 229, 1016–1027. [Google Scholar] [CrossRef]
  59. Kwan, S.T.C.; King, J.H.; Yan, J.; Jiang, X.; Wei, E.; Fomin, V.G.; Roberson, M.S.; Caudill, M.A. Maternal choline supplementation during murine pregnancy modulates placental markers of inflammation, apoptosis and vascularization in a fetal sex-dependent manner. Placenta 2017, 53, 57–65. [Google Scholar] [CrossRef]
  60. King, J.H.; Kwan, S.T.C.; Yan, J.; Jiang, X.; Fomin, V.G.; Levine, S.P.; Wei, E.; Roberson, M.S.; Caudill, M.A. Maternal Choline Supplementation Modulates Placental Markers of Inflammation, Angiogenesis, and Apoptosis in a Mouse Model of Placental Insufficiency. Nutrients 2019, 11, 374. [Google Scholar] [CrossRef]
  61. Hutzler, J.S.; Klein, H.R.; Brenna, J.T.; Kwan, S.T.C.; King, J.H.; Yan, J.; Wang, Z.; Jiang, X.; Roberson, M.S.; Caudill, M.A. Maternal Choline Supplementation Modulates Placental Nutrient Transport and Metabolism in Late Gestation of Mouse Pregnancy. J. Nutr. 2017, 147, 2083–2092. [Google Scholar]
  62. King, J.H.; Kwan, S.T.C.; Yan, J.; Klatt, K.C.; Jiang, X.; Roberson, M.S.; Caudill, M.A. Maternal Choline Supplementation Alters Fetal Growth Patterns in a Mouse Model of Placental Insufficiency. Nutrients 2017, 9, 765. [Google Scholar] [CrossRef]
  63. Nam, J.; Greenwald, E.; Jack-Roberts, C.; Ajeeb, T.T.; Malysheva, O.V.; Caudill, M.A.; Axen, K.; Saxena, A.; Semernina, E.; Nanobashvili, K.; et al. Choline prevents fetal overgrowth and normalizes placental fatty acid and glucose metabolism in a mouse model of maternal obesity. J. Nutr. Biochem. 2017, 49, 80–88. [Google Scholar] [CrossRef]
  64. Jack-Roberts, C.; Joselit, Y.; Nanobashvili, K.; Bretter, R.; Malysheva, O.V.; Caudill, M.A.; Saxena, A.; Axen, K.; Gomaa, A.; Jiang, X. Choline Supplementation Normalizes Fetal Adiposity and Reduces Lipogenic Gene Expression in a Mouse Model of Maternal Obesity. Nutrients 2017, 9, 899. [Google Scholar] [CrossRef]
  65. Nanobashvili, K.; Jack-Roberts, C.; Bretter, R.; Jones, N.; Axen, K.; Saxena, A.; Blain, K.; Jiang, X. Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts. Nutrients 2018, 10, 1507. [Google Scholar] [CrossRef]
  66. Jansson, N.; Rosario, F.J.; Gaccioli, F.; Lager, S.; Jones, H.N.; Roos, S.; Jansson, T.; Powell, T.L. Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. J. Clin. Endocrinol. Metab. 2013, 98, 105–113. [Google Scholar] [CrossRef]
  67. Rosario, F.J.; Powell, T.L.; Jansson, T. Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016, 310, R87–R93. [Google Scholar] [CrossRef] [Green Version]
  68. Joselit, Y.; Nanobashvili, K.; Jack-Roberts, C.; Greenwald, E.; Malysheva, O.V.; Caudill, M.A.; Saxena, A.; Jiang, X. Maternal betaine supplementation affects fetal growth and lipid metabolism of high-fat fed mice in a temporal-specific manner. Nutr. Diabetes 2018, 8, 41. [Google Scholar] [CrossRef]
  69. Carlin, J.; George, R.; Reyes, T.M. Methyl Donor Supplementation Blocks the Adverse Effects of Maternal High Fat Diet on Offspring Physiology. PLoS ONE 2013, 8, e63549. [Google Scholar] [CrossRef]
  70. McCann, J.C.; Hudes, M.; Ames, B.N. An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosci. Biobehav. Rev. 2006, 30, 696–712. [Google Scholar] [CrossRef]
  71. Meck, W.H.; Williams, C.L. Metabolic imprinting of choline by its availability during gestation: Implications for memory and attentional processing across the lifespan. Neurosci. Biobehav. Rev. 2003, 27, 385–399. [Google Scholar] [CrossRef]
  72. Blusztajn, J.K.; Slack, B.E.; Mellott, T.J. Neuroprotective Actions of Dietary Choline. Nutrients 2017, 9, 815. [Google Scholar] [CrossRef]
  73. Mudd, A.T.; Getty, C.M.; Dilger, R.N. Maternal Dietary Choline Status Influences Brain Gray and White Matter Development in Young Pigs. Curr. Dev. Nutr. 2018, 2, nzy015. [Google Scholar] [CrossRef] [Green Version]
  74. Getty, C.M.; Dilger, R.N. Moderate Perinatal Choline Deficiency Elicits Altered Physiology and Metabolomic Profiles in the Piglet. PLoS ONE 2015, 10, e0133500. [Google Scholar] [CrossRef]
  75. Mudd, A.T.; Getty, C.M.; Sutton, B.P.; Dilger, R.N. Perinatal choline deficiency delays brain development and alters metabolite concentrations in the young pig. Nutr. Neurosci. 2016, 19, 425–433. [Google Scholar] [CrossRef]
  76. Albright, C.D.; Tsai, A.Y.; Friedrich, C.B.; Mar, M.-H.; Zeisel, S.H. Choline availability alters embryonic development of the hippocampus and septum in the rat. Dev. Brain Res. 1999, 113, 13–20. [Google Scholar] [CrossRef]
  77. Trujillo-Gonzalez, I.; Friday, W.B.; Munson, C.A.; Bachleda, A.; Weiss, E.R.; Alam, N.M.; Sha, W.; Zeisel, S.H.; Surzenko, N. Low availability of choline in utero disrupts development and function of the retina. FASEB J. 2019, 33, 9194–9209. [Google Scholar] [CrossRef]
  78. Gould, R.M.; Dawson, R.M. Incorporation of newly formed lecithin into peripheral nerve myelin. J. Cell Biol. 1976, 68, 480–496. [Google Scholar] [CrossRef]
  79. Cermak, J.M.; Holler, T.; Jackson, D.A.; Blusztajn, J.K. Prenatal availability of choline modifies development of the hippocampal cholinergic system. FASEB J. 1998, 12, 349–357. [Google Scholar] [CrossRef] [Green Version]
  80. Li, Q.; Guo-Ross, S.; Lewis, D.V.; Turner, D.; White, A.M.; Wilson, W.A.; Swartzwelder, H.S. Dietary Prenatal Choline Supplementation Alters Postnatal Hippocampal Structure and Function. J. Neurophysiol. 2004, 91, 1545–1555. [Google Scholar] [CrossRef]
  81. Glenn, M.J.; Gibson, E.M.; Kirby, E.D.; Mellott, T.J.; Blusztajn, J.K.; Williams, C.L. Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats. Eur. J. Neurosci. 2007, 25, 2473–2482. [Google Scholar] [CrossRef] [Green Version]
  82. Jones, J.; Meck, W.H.; Williams, C.L.; A Wilson, W.; Swartzwelder, H.; Iii, J.J. Choline availability to the developing rat fetus alters adult hippocampal long-term potentiation. Dev. Brain Res. 1999, 118, 159–167. [Google Scholar] [CrossRef]
  83. Mellott, T.J.; Huleatt, O.M.; Shade, B.N.; Pender, S.M.; Liu, Y.B.; Slack, B.E.; Blusztajn, J.K. Perinatal Choline Supplementation Reduces Amyloidosis and Increases Choline Acetyltransferase Expression in the Hippocampus of the APPswePS1dE9 Alzheimer’s Disease Model Mice. PLoS ONE 2017, 12, e0170450. [Google Scholar]
  84. Velazquez, R.; Ferreira, E.; Winslow, W.; Dave, N.; Piras, I.S.; Naymik, M.; Huentelman, M.J.; Tran, A.; Caccamo, A.; Oddo, S. Maternal choline supplementation ameliorates Alzheimer’s disease pathology by reducing brain homocysteine levels across multiple generations. Mol. Psychiatry 2019. [Google Scholar] [CrossRef]
  85. Thomas, J. Perinatal choline supplementation attenuates behavioral alterations associated with neonatal alcohol exposure in rats. Neurotoxicology Teratol. 2004, 26, 35–45. [Google Scholar] [CrossRef]
  86. Thomas, J.D.; Abou, E.J.; Dominguez, H.D. Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats. Neurotoxicology Teratol. 2009, 31, 303–311. [Google Scholar] [CrossRef] [Green Version]
  87. Thomas, J.D.; Tran, T.D. Choline supplementation mitigates trace, but not delay, eyeblink conditioning deficits in rats exposed to alcohol during development. Hippocampus 2012, 22, 619–630. [Google Scholar] [CrossRef]
  88. Langley, E.A.; Krykbaeva, M.; Blusztajn, J.K.; Mellott, T.J. High maternal choline consumption during pregnancy and nursing alleviates deficits in social interaction and improves anxiety-like behaviors in the BTBR T+Itpr3tf/J mouse model of autism. Behav. Brain Res. 2015, 278, 210–220. [Google Scholar] [CrossRef]
  89. Orenbuch, A.; Fortis, K.; Taesuwan, S.; Yaffe, R.; Caudill, M.A.; Golan, H.M. Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among. Front. Neurosci. 2019, 13, 383. [Google Scholar] [CrossRef]
  90. Velázquez, R.; Ash, J.A.; Powers, B.E.; Kelley, C.M.; Strawderman, M.; Luscher, Z.I.; Ginsberg, S.D.; Mufson, E.J.; Strupp, B.J. Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome. Neurobiol. Dis. 2013, 58, 92–101. [Google Scholar] [CrossRef] [Green Version]
  91. Powers, B.E.; Kelley, C.M.; Velazquez, R.; Ash, J.A.; Strawderman, M.S.; Alldred, M.J.; Ginsberg, S.D.; Mufson, E.J.; Strupp, B.J. Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring. Neuroscience 2017, 340, 501–514. [Google Scholar] [CrossRef]
  92. Ash, J.A.; Velázquez, R.; Kelley, C.M.; Powers, B.E.; Ginsberg, S.D.; Mufson, E.J.; Strupp, B.J. Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice. Neurobiol. Dis. 2014, 70, 32–42. [Google Scholar] [CrossRef] [Green Version]
  93. Yan, J.; Ginsberg, S.D.; Powers, B.; Alldred, M.J.; Saltzman, A.; Strupp, B.J.; Caudill, M.A. Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice. FASEB J. 2014, 28, 4312–4323. [Google Scholar] [CrossRef]
  94. Kennedy, B.C.; Dimova, J.G.; Siddappa, A.J.M.; Tran, P.V.; Gewirtz, J.C.; Georgieff, M.K. Prenatal Choline Supplementation Ameliorates the Long-Term Neurobehavioral Effects of Fetal-Neonatal Iron Deficiency in Rats. J. Nutr. 2014, 144, 1858–1865. [Google Scholar] [CrossRef] [Green Version]
  95. Tran, P.V.; Kennedy, B.C.; Pisansky, M.T.; Won, K.-J.; Gewirtz, J.C.; A Simmons, R.; Georgieff, M.K. Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency–Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus. J. Nutr. 2016, 146, 484–493. [Google Scholar] [CrossRef]
  96. Strupp, B.J.; Powers, B.E.; Velazquez, R.; Ash, J.A.; Kelley, C.M.; Alldred, M.J.; Strawderman, M.; Caudill, M.A.; Mufson, E.J.; Ginsberg, S.D. Maternal choline supplementation: A potential prenatal treatment for Down syndrome and Alzheimer’s disease. Curr. Alzheimer Res. 2016, 13, 97–106. [Google Scholar] [CrossRef]
  97. Bekdash, R.A.; Zhang, C.; Sarkar, D.K. Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in β-endorphin-producing POMC neurons of the hypothalamus. Alcohol Clin. Exp. Res. 2013, 37, 1133–1142. [Google Scholar] [CrossRef]
  98. Otero, N.K.H.; Thomas, J.D.; Saski, C.A.; Xia, X.; Kelly, S.J. Choline supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development. Alcohol. Clin. Exp. Res. 2012, 36, 1701–1709. [Google Scholar] [CrossRef]
  99. Resseguie, M.; Song, J.; Niculescu, M.D.; Da Costa, K.-A.; Randall, T.A.; Zeisel, S.H. Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J. 2007, 21, 2622–2632. [Google Scholar] [CrossRef]
  100. Yan, J.; Jiang, X.; West, A.A.; Perry, C.A.; Malysheva, O.V.; Devapatla, S.; Pressman, E.; Vermeylen, F.; Stabler, S.P.; Allen, R.H.; et al. Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans. Am. J. Clin. Nutr. 2012, 95, 1060–1071. [Google Scholar] [CrossRef] [Green Version]
  101. Schaible, T.D.; Harris, R.A.; Dowd, S.E.; Smith, C.W.; Kellermayer, R. Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum. Mol. Genet. 2011, 20, 1687–1696. [Google Scholar] [CrossRef] [Green Version]
  102. Hollingsworth, J.W.; Maruoka, S.; Boon, K.; Garantziotis, S.; Li, Z.; Tomfohr, J.; Bailey, N.; Potts, E.N.; Whitehead, G.; Brass, D.M.; et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J. Clin. Investig. 2008, 118, 3462–3469. [Google Scholar] [CrossRef] [Green Version]
  103. Giudicelli, F.; Brabant, A.L.; Grit, I.; Parnet, P.; Amarger, V. Excess of methyl donor in the perinatal period reduces postnatal leptin secretion in rat and interacts with the effect of protein content in diet. PLoS ONE 2013, 8, e68268. [Google Scholar] [CrossRef]
  104. Cho, C.E.; Caudill, M.A. Trimethylamine- N -Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? Trends Endocrinol. Metab. 2017, 28, 121–130. [Google Scholar] [CrossRef]
  105. Klatt, K.C.; Caudill, M.A. Pressing the trimethylamine N-oxide narrative. AME Med. J. 2017, 2, 132. [Google Scholar] [CrossRef]
Nutrients 11 01823 g001 550
Figure 1. A simplified diagram of the metabolic fate of maternal dietary choline and its delivery to the developing fetus. In the liver, choline can be used to make phosphatidylcholine (PC) through the cytidine diphosphate (CDP)-choline pathway (CDP-PC), or it can be oxidized to betaine and serve as a source of methyl groups for PC synthesis via the de novo phosphatidylethanolamine N-methyltransferase (PEMT) pathway (PEMT-PC). Both pathways are upregulated during the third trimester of pregnancy, but PEMT-derived PC is preferentially partitioned to the developing fetus. CM, chylomicron; MET, methionine; PE, phosphatidylethanolamine; SAM, S-adenosylmethionine; VLDL, very low-density lipoprotein.
Figure 1. A simplified diagram of the metabolic fate of maternal dietary choline and its delivery to the developing fetus. In the liver, choline can be used to make phosphatidylcholine (PC) through the cytidine diphosphate (CDP)-choline pathway (CDP-PC), or it can be oxidized to betaine and serve as a source of methyl groups for PC synthesis via the de novo phosphatidylethanolamine N-methyltransferase (PEMT) pathway (PEMT-PC). Both pathways are upregulated during the third trimester of pregnancy, but PEMT-derived PC is preferentially partitioned to the developing fetus. CM, chylomicron; MET, methionine; PE, phosphatidylethanolamine; SAM, S-adenosylmethionine; VLDL, very low-density lipoprotein.
Nutrients 11 01823 g001
Nutrients 11 01823 g002 550
Figure 2. An overview of the effects of maternal choline intake during pregnancy on physiological processes and health outcomes.
Figure 2. An overview of the effects of maternal choline intake during pregnancy on physiological processes and health outcomes.
Nutrients 11 01823 g002
Table
Table 1. Human studies with a focus on maternal choline intake (or status) and pregnancy and child health outcomes (in chronological order).
Table 1. Human studies with a focus on maternal choline intake (or status) and pregnancy and child health outcomes (in chronological order).
StudyDesignIntervention/Choline Marker MeasurementPregnancy and Child Health OutcomesReferences
Shaw et al. 2004Case-controlMaternal dietary choline intake during the 3 months before conceptionReduced neural tube defect (NTD) risk with higher maternal choline intakes (n = 424 NTD and 440 control)[43]
Signore et al. 2008Prospective cohortMaternal serum total and free choline throughout gestation and cord blood choline concentrationsNo association between child intelligence quotient (IQ) scores at 5 years of age and maternal or cord blood choline (n = 404 maternal-child pairs) [44]
Shaw et al. 2009Prospective case-controlSerum total choline concentrations during the gestational week 15–18Reduced NTD risk with higher serum choline concentrations (n = 80 NTD and 409 control)[45]
Wu et al. 2012Prospective cohortMaternal plasma free choline at gestational week 16 Better cognitive scores in 18-month-old infants with higher maternal plasma free choline levels (n = 154 maternal-child pairs)[46]
Villamor et al. 2012Prospective cohortMaternal dietary choline intake in the 1st and 2nd trimester of pregnancyNo association between cognitive performance in 3-year-old children and maternal choline intake (n = 1210)[47]
Jiang et al. 2012 aRandomized clinical trial (RCT)Controlled feeding of 930 versus 480 mg choline/day for 12 weeks during 3rd trimester of pregnancyHigher placental CRH promoter methylation and lower cord blood cortisol concentrations in the 930 mg/d (n = 13) versus 480 mg/day (n = 13) choline intake group.[38]
Cheatham et al. 2012RCTPhosphatidylcholine (PC) supplement (750 mg choline/day) from 2nd trimester of pregnancy to 90 days postpartumNo effect on development or memory in 10 or 12-month-old infants (intervention group n = 49, placebo group n = 50)[48]
Boeke et al. 2013Prospective cohortMaternal dietary choline intake in the 2nd trimester of pregnancyBetter visual memory in 7-year-old children with top interquartile dietary choline intake during pregnancy (n = 895)[49]
Jiang et al. 2013 aRCTControlled feeding of 930 versus 480 mg choline/day for 12 weeks during 3rd trimester of pregnancyLower placental sFlt1 mRNA expression and maternal serum sFLT1 levels in the 930 mg/day (n = 13) versus 480 mg/d (n = 13) choline intake group[50]
Ross et al. 2013 bRCTPC supplement (900 mg choline/day) from 2nd trimester of pregnancy until delivery; 100mg/day of PC to infants until 3 months of ageGreater attention development in 5-week-old infants in the intervention group (n = 36) versus control (n = 40) [51]
Ross et al. 2016 bRCTPC supplement (900 mg choline/day) from 2nd trimester of pregnancy until delivery; 100mg/day of PC to infants until 3 months of ageReduced attentional problems and social withdrawal in children at 40 months of age in the intervention group (n = 23) versus control (n = 26) [52]
Caudill et al. 2018 aRCTControlled feeding of 930 versus 480 mg choline/day for 12 weeks during 3rd trimester of pregnancyFaster information processing speed in infants during 4–13 months in the 930 (n = 12) versus 480 mg/day group (n = 12)[53]
Jacobson et al. 2018RCT2 g choline/day or placebo from mid-pregnancy until delivery among heavy alcohol drinkersBetter eyeblink conditioning in infants at 6.5 months, higher novelty preference scores at 12 months, and more catch-up growth at both time points in the choline treated group (n = 32) versus control (n = 31)[54]
Freedman et al. 2018Prospective cohortSerum-free choline and betaine concentrations at week 16 of gestationImproved development of cerebral inhibition in newborns and behavioral regulation in 1-year-old infants born to infected mothers (n = 66) with higher gestational serum choline concentrations.[55]
Bahnfleth et al. 2019 aRCTControlled feeding of 930 versus 480 mg choline/day for 12 weeks during 3rd trimester of pregnancyBetter performance on a task of color-location memory at age 7 years in the 930 mg choline/day (n = 11) versus 480 choline mg/day (n = 9) choline intake group.[56]
a These articles are based on the same controlled feeding study; b These articles are based on the same RCT.

Share and Cite

MDPI and ACS Style

Korsmo, H.W.; Jiang, X.; Caudill, M.A. Choline: Exploring the Growing Science on Its Benefits for Moms and Babies. Nutrients 2019, 11, 1823. https://doi.org/10.3390/nu11081823

AMA Style

Korsmo HW, Jiang X, Caudill MA. Choline: Exploring the Growing Science on Its Benefits for Moms and Babies. Nutrients. 2019; 11(8):1823. https://doi.org/10.3390/nu11081823

Chicago/Turabian Style

Korsmo, Hunter W., Xinyin Jiang, and Marie A. Caudill. 2019. "Choline: Exploring the Growing Science on Its Benefits for Moms and Babies" Nutrients 11, no. 8: 1823. https://doi.org/10.3390/nu11081823

APA Style

Korsmo, H. W., Jiang, X., & Caudill, M. A. (2019). Choline: Exploring the Growing Science on Its Benefits for Moms and Babies. Nutrients, 11(8), 1823. https://doi.org/10.3390/nu11081823

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop