Choline
IUPAC name 2-hydroxy-N,N,N-trimethylethanaminium
Other names Bilineurine, (2-Hydroxyethyl)trimethylammonium
Identifiers
CAS number	62–49–7 Y
PubChem	6209
ChemSpider	299 Y
UNII	N91BDP6H0X Y
EC-number	200–655–4
DrugBank	DB00122
KEGG	C00114 Y
ChEBI	CHEBI:15354 Y
ChEMBL	CHEMBL920 Y
Beilstein Reference	1736748
Gmelin Reference	324597
Jmol-3D images	Image 1
SMILES C[N+](C)(C)CCO
InChI InChI=1S/C5H14NO/c1-6(2,3)4-5-7/h7H,4-5H2,1-3H3/q+1 Y Key: OEYIOHPDSNJKLS-UHFFFAOYSA-N Y InChI=InChI=1S/C5H14NO/c1-6(2,3)4-5-7/h7H,4-5H2,1-3H3/q+1
Properties
Molecular formula	C5 H14 N O
Molar mass	104.17080
Boiling point	305
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Choline is a water-soluble essential nutrient.^{[1][2][3][4][5]} It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. (X⁻ on the right denotes an undefined counteranion).

The cation appears in the head groups of phosphatidylcholine and sphingomyelin, two classes of phospholipid that are abundant in cell membranes. Choline is the precursor molecule for the neurotransmitter acetylcholine which is involved in many functions including memory and muscle control.

Choline must be consumed through the diet in order for the body to remain healthy.^[6] It is used in the synthesis of the constructional components in the body's cell membranes. Despite the perceived benefits of choline, dietary recommendations have discouraged people from eating certain high choline foods, such as egg and fatty meats. The 2005 National Health and Nutrition Examination Survey stated that only 2% of postmenopausal women consume the recommended intake for choline.^[7]

History[link]

Choline was discovered by Adolph Strecker in 1864 and chemically synthesized in 1866. In 1998 choline was classified as an essential nutrient by the Food and Nutrition Board of the Institute of Medicine (USA).^[8]

Choline's importance as a nutrient was first appreciated in the early research on insulin functions when choline was found to be the necessary nutrient in preventing fatty liver. In 1975 scientists discovered that the administration of choline increased the synthesis and release of acetylcholine by neurons. These discoveries lead to the increased interest in dietary choline and brain function.

Today, we know Choline to be a dietary nutrient important for all cells to function normally. Choline is required for synthesis of essential components of membranes and is an important source of labile methyl groups.

Recent research[link]

A recent study in Nov 2010 by Leslie M. Fischer, Kerry Ann da Costa, Lester Kwock, Joseph Galanko, and Steven Zeisel was to test postmenopausal women with low estrogen levels and see if they were more susceptible to the risk of organ dysfunction if not given a sufficient choline filled diet. When deprived of choline in their diet almost 80% of the men and postmenopausal women developed liver or muscle damage. The study also found that young women can supply more choline because pregnancy is a time when the body's demand for choline are highest. Choline is particularly used to support the fetus's developing nervous system.^[7]

Chemistry[link]

Choline is a quaternary saturated amine with the chemical formula (CH₃)₃N⁺CH₂CH₂OHX⁻, where X⁻ is a counterion such as chloride (see choline chloride), hydroxide or tartrate. Choline chloride can form a low-melting deep eutectic solvent mixture with urea with unusual properties. The salicylate salt is used topically for pain relief of aphthous ulcers.^{[citation needed]}

Choline hydroxide[link]

Choline hydroxide is one of the class of phase transfer catalysts that are used to carry the hydroxide ion into organic systems, and, therefore, is considered a strong base. It is the least costly phase transfer catalyst, and is used as a cheap method of stripping photoresists in circuit boards. Choline hydroxide is not completely stable, and it slowly breaks down into trimethylamine.^[9]

Role in humans[link]

Physiology[link]

Choline metabolism. (Choline is green box at left, second from the bottom.)

Choline and its metabolites are needed for three main physiological purposes: structural integrity and signaling roles for cell membranes, cholinergic neurotransmission (acetylcholine synthesis), and a major source for methyl groups via its metabolite, trimethylglycine (betaine) which participates in the S-adenosylmethionine (SAMe) synthesis pathways.^{[citation needed]}

Choline deficiency signs[link]

Most common signs of choline deficiencies are fatty liver and hemorrhagic kidney necrosis. Dietary intake of a choline full diet can reduce the severity of the deficiency. A study of this on animals has created some controversy due to the inconsistency in dietary modifying factors.^[10] Choline deficiency in animals compromises renal function. Choline low diets can also cause infertility, growth impairment, bone abnormalities, and hypertension. Choline deficiency is considered to both initiate and promote cancer activities.^{[citation needed]}

Required choline levels in diet were determined by feeding healthy humans a choline-deficient diet until they developed biochemical changes consistent with choline deficiency.^{[citation needed]}

Fish odor syndrome[link]

Choline is a precursor to trimethylamine, which some persons are not able to break down due to a genetic disorder called trimethylaminuria. Persons suffering from this disorder may suffer from a strong fishy or otherwise unpleasant body odor, due to the body's release of odorous trimethylamine. A body odor will occur even on a normal diet – i.e., one that is not particularly high in choline. Persons with trimethylaminuria are advised to restrict the intake of foods high in choline; this may help to reduce the sufferer's body odor.^[11]

Groups at risk for choline deficiency[link]

Vegetarians, vegans, endurance athletes, and people who drink a lot of alcohol may be at risk for choline deficiency and may benefit from choline supplements.^[12]

In general, people who do not eat many whole eggs may have to pay close attention to get enough choline in their diets.^[13] Studies on a number of different populations have found that the average intake of choline was below the adequate intake (AI).^[2][14]

The choline researcher Dr. Steven Zeisel wrote: "A recent analysis of data from NHANES 2003–2004 revealed that for [American] older children, men, women and pregnant women, mean choline intakes are far below the AI. Ten percent or fewer had usual choline intakes at or above the AI."^[2]

Food sources of choline[link]

The adequate intake (AI) of choline is 425 mg (milligrams) per day for adult women; higher for pregnant and breastfeeding women. The AI for adult men is 550 mg/day. There are also AIs for children and teens.^[15]

Besides cauliflower, other cruciferous vegetables may also be good sources of choline.^[20]

Sinapine is an alkaloidal amine found in black mustard seeds. It is considered a choline ester of sinapic acid.^[21]

Choline and other nutrient values for many foods can be obtained online.^{[a 1]}

Necessary choline for humans[link]

The average choline dietary in an adult human is about 7–10 mmol/day. A human infant consumes a great amount of choline from breast milk, which contains 1.5 mmol/L choline. An infant can ingest about 750μmol choline. It is for this reason choline has routinely been added to baby formula. The choline demand in a normal adult is likely to be smaller than for an infant as most of the infants choline needs to be used to develop organs in its growing body, especially the brain.

Health effects of dietary choline[link]

Choline deficiency may play a role in liver disease, atherosclerosis, and possibly neurological disorders,^[2] One symptom of choline deficiency is an elevated level of the liver enzyme ALT.^[22]

It is particularly important for pregnant women to get enough choline, since low choline intake may raise the rate of neural tube defects in infants, and may affect their child's memory. One study found that higher dietary intake of choline shortly before and after conception was associated with a lower risk of neural tube defects.^[23] If low choline intake causes an elevated homocysteine level, it raises the risk for preeclampsia, premature birth, and very low birth weight.^[2]

Women with diets richer in choline may have a lower risk for breast cancer,^[24][25] but other studies found no association.^[26][27]

There is some evidence to suggest that choline is anti-inflammatory. In the ATTICA study, higher dietary intake of choline was associated with lower levels of inflammatory markers.^[28] A small study found that choline supplements reduced symptoms of allergic rhinitis.^[29]

Despite its importance in the central nervous system as a precursor for acetylcholine and membrane phosphatidylcholine, the role of choline in mental illness has been little studied. In a large population-based study, blood levels of choline were inversely correlated with anxiety symptoms in subjects aged 46–49 and 70–74 years. However, there was no correlation between depression and choline level in this study.^[30]

The adequate intake is intended to be high enough to be adequate for almost all healthy people.^[31] Many people do not develop deficiency symptoms when consuming less than the Adequate Intake of choline.^[2] The human body synthesizes some of the choline it needs, and people vary in their need for dietary choline.^[32] In one study, premenopausal women were less sensitive to a low-choline diet than men or postmenopausal women.^[32]

However, the Adequate Intake may not be enough for some people. In the same study, 6 out of 26 men developed choline deficiency symptoms while consuming the Adequate Intake (and no more) of choline.^[32] The Adequate Intake was less than the optimal intake for the male subjects in another study.^[33]

High dietary intake of choline was associated with an increased risk of colon adenomas (polyps), for women in the Nurses' Health Study. However, this could represent effects of other components in the foods from which choline was obtained.^[34] Dietary choline intake was not associated with increased risk of colorectal cancer, for men in the Health Professionals Follow-up Study.^[35]

Similar to the effect on memory of choline consumption in utero or as a neonate discussed below, adult rodent dietary choline deficiency has been demonstrated to exacerbate memory loss and diets high in choline appear to diminish memory loss. Further, choline supplemented older mice performed as well as young three-month-old mice and it was noted that supplemented mice had more dendritic spines per neuron within the hippocampus. However, no similar work has been done in humans.^[36]

Choline as a dietary supplement[link]

The most often available choline supplement is lecithin, derived from soy or egg yolks, often used as a food additive. Phosphatidylcholine is also available as a supplement, in pill or powder form. Supplementary choline is also available as choline chloride, which comes as a liquid due to its hydrophilic properties. Choline chloride is sometimes preferred as a supplement because phosphatidylcholine can have gastrointestinal side effects.^[37]

It is well established that supplements of methyl group transfer vitamins B₆, B₁₂, folic acid reduce the blood titer of homocysteine and so may prevent heart disease.^[38] Choline or betaine supplements also may reduce homocysteine.^[39] Choline is a necessary source of methyl groups for methyl group transfer. Supplements of lecithin/choline were found to reduce heart disease in laboratory studies.^{[citation needed]} The reduction in heart disease with lecithin supplements may however relate more to the cholesterol-carrying capacity of lecithin than to the methyl group transfer role of choline.^[specify]

Choline supplements are often taken as a form of 'smart drug' or nootropic, due to the role that the neurotransmitter acetylcholine plays in various cognition systems within the brain. Choline is a chemical precursor or "building block" needed to produce the neurotransmitter acetylcholine, and research suggests that memory, intelligence, and mood are mediated at least in part by acetylcholine metabolism in the brain.^{[citation needed]} In a study on rats, a correlation was shown between choline intake during pregnancy and mental task performance of the offspring;^[40] but the same correlation has not been shown in humans.^[41] However, this human study admits that "[w]omen in the current study consumed their usual diets. They were not eating choline-enriched diets and were not receiving choline supplementation. Therefore, our results indicate that choline concentrations in a physiologic range observed among women consuming a regular diet during pregnancy are not related to IQ in their offspring. We cannot rule out the possibility that choline supplementation could have an IQ effect."^[41]

Initial studies on Rhesus macaques found that choline supplementation had adverse effects on the fetuses of smoking or nicotine consuming mothers. When consumed with nicotine, choline protected some regions of the fetal brain from damage, but worsened nicotine's effects in other regions. This indicates that choline, ordinarily thought to be neuroprotectant, may worsen some of the adverse effects of nicotine.^[42]

The compound's quaternary amine renders it lipid-insoluble, which might suggest it would be unable to cross the blood–brain barrier. However, despite choline's lipid insolubility, a choline transporter that allows transport across the blood–brain barrier exists.^[43] The efficacy of these supplements in enhancing cognitive abilities is a topic of continuing debate.

The Food and Drug Administration (FDA) requires that infant formula not made from cow's milk be supplemented with choline.^[44]

Due to its role in lipid metabolism, choline has also found its way into nutritional supplements that claim to reduce body fat; but there is little or no evidence to prove that it has any effect on reducing excess body fat, or that taking high amounts of choline will increase the rate at which fat is metabolised.^{[citation needed]}

Pharmaceutical uses[link]

Choline is used in the treatment of liver disorders,^[45][46] Alzheimer's disease,^[47] and bipolar disorder.^[48]

Some studies show that as a supplement, choline is also used in treating hepatitis, glaucoma,^[49] atherosclerosis, and, possibly, neurological disorders.^[2]

Choline has also been proven to have a positive effect on those suffering from alcoholism.^[50][51]

The current NIH funded research study COBRIT is gathering data regarding potential benefit of longterm citicoline treatment for recovery after traumatic brain injury.

Medical imaging[link]

Maximum intensity projection of a PET/CT with choline. Note the physiologic accumulation in the liver, pancreas, kidney, bladder, spleen, bone marrow and salivary glands. Bone metastasis in the left pubic bone.

Choline can be labelled with carbon-11 or fluorine-18 which are radioactive positron emittors enabling medical imaging on a positron emission tomography (PET) scanner. This is usually performed by a nuclear medicine physician. Uses include imaging prostate and breast cancer.

Pregnancy and brain development[link]

Introduction

Choline may be produced both de novo (from scratch) by methylation of phosphatidylethanolamine by N-methyltranferase (PEMT) to form phosphatidylcholine in the liver or it may be consumed from the diet. It has been demonstrated that both de novo production and dietary consumption are necessary as humans eating diets that lack choline develop fatty liver, liver damage, and muscle damage. However, because of the close interplay between choline, folate, methionine, and vitamin B12, (whose pathways overlap)the function of choline can be complex.

To begin with, methionine can be formed two ways, either from methyl groups derived from folate, or from methyl groups derived from betaine (which gets its methyl groups from choline). Changes in one of these pathways is compensated for by the other,and if these pathways do not adequately supply methyl groups to produce methionine, the precursor to methionine, homocysteine, rises.

Choline in food exists as either a free or esterified form (choline bound to another compound, such as phosphytidylcholine). Although all forms are most likely usable, there is some evidence that they are differentially bioavaliable (able to be used by the body). Lipid soluble forms (like phosphytidylcholine) bypass the liver once absorbed, while water soluble forms (such as free choline) enter the liver portal circulation and are generally absorbed by the liver.^[52] Both pregnancy and lactation increase demand for choline dramatically. This demand may be met by upregulation of PEMT via increasing estrogen levels to produce more choline de novo, but even with increased PEMT activity the demand for choline is still so high that bodily stores are generally depleted. This is exemplified by the observation that Pemt -/- mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline.^[53]

While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient in to the tissue, where it is then stored in various forms, most interestingly as acetylcholine, (an uncommon occurrence outside of neural tissue). The fetus itself is exposed to a very high choline environment as a result, and choline concentrations in amniotic fluid can be ten times higher than in maternal blood. It is assumed that this high concentration allows choline to be abundantly available to tissues and cross the blood brain barrier effectively.^[53]

Functions in the fetus

Choline is in high demand during pregnancy as a substrate for building cellular membranes, (rapid fetal and mother tissue expansion), increased need for one carbon moieties (a substrate for addition of methylation to DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions).^[54][55][56] In particular, there is interest in the impact of choline consumption on the brain. This stems from choline's use as a material for making cellular membranes, (particularly in making phosphotidylcholine). Human brain growth is most rapid during the third trimester of pregnancy and continues to be rapid to approximately five years of age.^[57] During this time there is high demand for sphingomyelin, which is made from phosphytidyl choline, (and thus from choline), because this material is used to myelinate (insulate) nerve fibers.^[58] Choline is also in demand for the production of the neurotransmitter acetylcholine, which can influence the structure and organization of brain regions, neurogenesis, myelination, and synapse formation. Acetylcholine is even present in the placenta and may help control cell proliferation/differentiation (increases in cell number and changes of multi use cells in to dedicated cellular functions) and parturition.^{[59][60][61][62]} Choline may also impact methylation of CpG dinucleotides in DNA in the brain – this methylation can change genome expression (which genes are turned on and which are turned off) and thus fetal programming (the act of arranging so that certain genes are by default turned off or turned on in the absence of external forces).^[63][64]

What choline does within the fetus is determined by choline's concentration. At low choline concentrations it is preferentially shunted towards making phospholids. As concentrations rise, free choline is converted to betain in liver mitochondria, and betaine is used as a source of methyl groups for DNA methylation, etc.^[65][66] However, should concentrations of choline decrease enough, the PEMT pathway is up regulated, (activated).^[67] The PEMT pathway allows for creation of new choline without consuming choline from the diet. This pathway has been shown to produce up to 30% of needed phosphotidylcholine.^[68] Interestingly, PEMT produced phosphytidyl choline tends to have longer less saturated fatty acids than that produced directly from choline via the CDP-choline pathway.^[69]

Concentration is also important in getting choline in to the brain for use to prevent neural nonclosure and poor brain development.^[52] Choline uptake in to the brain is controlled by a low-affinity (not particularly efficient) transporter located at the blood brain barrier. Transport occurs when arterial plasma choline concentrations increase above 14 umol/L, which can occur during a spike in choline concentration after consuming choline rich foods. Neurons, conversely, acquire choline by both high and low affinity transporters. Choline is stored as membrane bound phosphytidyl choline which can then be used for acetylcholine neurotransmitter synthesis later. Acetylcholine is formed as needed, travels across the synapse, and transmits the signal to the following neuron. Afterwards acetycholinesterase degrades it, and the free choline is taken up by a high affinity transporter in to the neuron again.^[70]

Neural tube closure

While folate is most well known for preventing neural tube nonclosure, (and this is the basis for its addition to prenatal vitamins), folate and choline metabolism are interrelated. Both choline and folate (with the help of vitamin B12) can act as methyl donors to homocysteine to form methionine, which can then go on to form SAM and act as a methyl donor for methylation of DNA. It has been demonstrated that dietary choline deficiency alone without concurrent folate deficiency can decrease SAM concentration, suggesting that both folate and choline important sources of methyl groups for SAM production.^[53] Inhibition of choline absorption and use is associated with neural tube defects in mice and it has been suggested this may also occur in humans.^[52] A retrospective case control study (a study collects data after the fact from cases that occur without the investigator causing them to occur) of 400 cases and 400 controls indicated that women with the lowest daily choline intake had a 4 fold greater risk of having a child with a neural tube defect than women in the highest quartile of intake.^[71]

Choline in utero and long-term memory

Maternal dietary consumption or lack of consumption of choline during late pregnancy in rodents was related to irreversible changes in hippocampal function in adult rodents, including changes in long term memory capacity. Increased consumption of choline in rodent dams by about four time dietary recommendations during days 11–17 of pregnancy increased hippocampal cell proliferation and decreased apoptosis (programmed cell death) of these cells in their fetuses. This may occur because in choline deficient cells in culture, and in fetal rodent brains from choline deficient dams, the promoter of CDKN3, a gene which inhibits cell proliferation in the brain, is not properly methylated. This leaves CDKN3 active, decreasing cell proliferation in the brain. Increased choline consumption by rodent dams has shown improved auditory and visuaspatial memory in offspring as well as preventing age-related memory decline as their offspring grew old. The capacity of choline consumption by dams to improve the memory of their offspring has been shown in a variety of memory tests, including: the radial-arm maze, Morris water maze, passive avoidance paradigms, and measures of attention. It has also been demonstrated in a variety of rat strains – including Sprague-Dawley and Long-Evans and in mice.This suggests that the effect of choline consumption on the fetus in utero is universal among rodents. However, the mechanism behind this response is not fully understood. It has been suggested that the effect of neonatal choline on memory comes from increasing the amount of choline in the brain and subsequently, the amount of acetylcholine that can be produced and released. However, the amount of choline that accumulates in the brain after consumption of choline by pregnant dams does not seem to be sufficient to change the acetylcholine release. Instead, it has been noted that choline consumption by dams increases phosphocholine and betaine in the fetal brain.

These findings are in rodents, a species with faster brain maturation and a more mature brain at birth than is typical for humans. In humans the brain continues to develop after birth, and does not become similar to its adult structure until around 4 years of age. It has been suggested that by feeding infants formula instead of milk, and presumably through differences in choline amount in the breast milk of mothers consuming different choline levels, the still developing brain of an infant may be impacted. This may, in part, contribute to the differences seen between individual adult humans in memory and recall.^[53]

Impact of genetic polymorphisms (genetic variation)

It has been observed that some men and women develop organ dysfunction when fed low choline diets, while others do not, and that there is a large range in choline requirements for optimal health, from 850 mg/70 kg/day to 550 mg/kg/day. This difference has been attributed to SNPs (single-nucleotide polymorphisms) in choline metabolic pathways, (SNPs change the RNA code, and can subsequently change the arrangement of the protein made from that RNA, leading to differences in protein function between the normal version and the SNP version). For example, folate pathway polymorphisms may limit the usability of folate for SAM production – thereby making a person more dependent on choline for SAM production. PEMT polymorphisms change the amount of choline that can be synthesized de novo, (increasing the amount of choline that must be supplied by the diet).

In one study, a common genetic polymorphism, MTHFDI (5,10 methylenetetrahydrofolate dehydrogenase1958A)in folate metabolsim made premenopausal women 15 times more likely to develop signs of choline deficiency on a low choline diet as non-carriers of the SNP (p < 0.0001). The impact of this SNP is quite large - 63% of the study population had at least one allele with the SNP. The MTHFD1 allele is believed to change the flux between 5,10-methylenetetrahydrofolate and 10-formyltetrahydrofolate, which influences the availability of 5-methl tetrahydrofolate for homocysteine methylation, (and subsequent methionine and then SAM production). This would mean more choline would be shunted towards methylation to make up for the lack of folate participation in the pathway.^[53] A real world application of this is that the risk of having a child with a neural tube defect is increased in mothers with the G1958A SNP in MTHFD1.^[72] Additionally, mice that are Mthfr -/- (lacking MTHFR) become choline deficient, suggesting that humans with genetic polymorphisms that alter the functionality of the enzyme may also have choline deficiency problems.

SNPs have also been found in PEMT (responsible for de novo choline production). Ziesel et al. located a SNP in the promoter region of the PEMT gene that was related to increased susceptibility to choline deficiency in women. Since sexual differences in the impact of this SNP were found, Ziesel suggests that this SNP alters the estrogen responsiveness of the promoter region of the PEMT gene. Ziesel et al. also located another SNP in exon 8 (the coding portion of a gene) of PEMT with 30% loss of function of PEMT and increased risk for nonalcoholic fatty liver disease as an end result.^[53]

It should be noted, however, that not all SNPs in choline/folate related genes have been shown to impact choline needs. C677T and A1298C polymorphisms in MTHFR and A80C polymorphism in the reduced folate carrier gene have not been found to be significant.

Choline and lactation[link]

Introduction to lactation

The human mammary gland is composed of several cell types, including adipose (fat cells), muscle, ductal epithelium, and mammary epithelium (referred to sometimes as lactocytes). The mammary epithelium is the site for excretion of raw materials in to the milk supply, including choline. This occurs, for the fat portion of the milk, by apocrine secretion, where vacoules containing materials bud off of the cell in to the lumen (storage) of the alveolus, (milk secretion gland). From here the milk will be released upon stimulation with oxytocin via suckling.^[73] It has been suggested that the mammary gland may have evolved from the innate immune system, and lactation may be connected to inflammation – based on the obersvation that inflammation signaling pathways, NF-κB and Jak/Stat are found both in inflammatory responses and lactation. If this is true, it highlights the role of the mammary gland not only as a source of energy, but also as a major contributor to preparing offspring for survival in the outside world.^[74]

Choline in milk

Choline can be found in milk as free choline, phosphocholine, glycerophosphocholine, sphingomyelin and phosphatidylcholine and choline levels within breast milk are correlated with choline levels in maternal blood.^[75][76] Choline consumed via breast milk has been shown to impact blood levels of choline in breast feeding infants – indicating that choline consumed in breast milk is entering the fetal system.^[76] Choline may enter the milk supply either directly from the maternal blood supply, or choline containing nutrients may be produced within the mammary epithelium.^[77] Choline reaches the milk through a transporter specific for choline from the maternal blood supply (against a concentration gradient) in to the mammary epithelial cells.^[78] At high concentrations, (concentrations greater than that typically seen in humans), choline can diffuse across the cell membrane in to the mammary epithelium cell. At more normal concentrations, it passes via what is believed to be a calcium/sodium dependent, phosphorylation related, active transporter in to the cell. It may also be produced within the mammary epithelium de novo via the PEMT pathway.^[79] Once choline containing milk has been consumed by the neonate, it is used for formation of acetylcholine, phosphatidylcholine, sphingomyelin, and choline plasmalogens for cell membrane production in mice, and the majority of the choline in milk is supplied as phosphatidylcholine (related perhaps to the release of already formed globules of cellular membrane during apocrine secretion of mammary epithelium produced nutrients). James also demonstrated that the hormone insulin may stimulate choline uptake into mouse mammary cells and prolactin encouraged choline incorporation in to lipids when cells were concurrently treated with insulin and cortisol.^[77]

Differences between full term and premature mothers and infants

Holmes-McNary et al. reports that choline content in mature breast milk from mothers delivering preterm was significantly lower than the choline content from mothers delivering at term. However, choline esters (choline containing compounds) did not differ in concentration between preterm and full term mothers.^[80] It has been suggested that mothers delivering before full term may not have adequate mammary development, and may not reach full mammary development by the time they begin producing mature milk.^[73] It is possible that choline content may be lower in preterm mothers because of this effect. However, Lucas et al. did find significant improvement at 18 months and at 7.5–8 years of age in IQ score among preterm infants that were fed breast milk via tube in comparison to those that were not fed breast milk, suggesting that even if the mammary gland may be "immature" breast milk produced by it still has benefit. Additionally, preterm infants fed formula prepared for term infants had lower mental performance than those fed formula prepared specifically for preterm infants, but this effect was diminished between preterm infants fed donated breast milk and those fed preterm formula. Further supporting this, Lucas et al. also found that of the factors examined, consumption of mothers' milk was the most significantly related to later IQ performance.^[81]

Additionally, a meta-analysis by Anderson et al. found that low-birth-weigh infants derived more benefit from breast feeding, (in terms of IQ score later in life) than did normal weight infants also being breast fed.^[82] Drane and Logemann summarize their meta-analysis of 24 studies by stating "an advantage in IQ to breast-fed infants of the order of five points for term infants and eight points for low birth weight infants [was observed]. Arguably, increases in IQ of these magnitudes would have relatively subtle impact at an individual level. However, the potential impact at a population level must also be considered."^[83]

Differences between breast milk and formula

Human milk is very rich in choline, however, formulas derived from other sources, particularly soy, have lower total choline concentrations than human milk, (and also lack other important nutrients, such as long chain polyunsatureated fatty acids, sialylated oligosaccharides, thyroid-stimulating hormone, neurotensin, nerve growth factor, and the enzymes lysozume and peroxidase).^[84][85][86] Bovine milk and bovine-derived formulas had similar or higher glycerophosphocholine to human milk and soy derived formulas had lower glycerophosphocholine content. Phosphatidylcholine and sphingomyelin concentrations were similar between bovine formulas and human milk, but soy-derived infant formulas had more phosphatidylcholine than human or bovine sources. Soy-derived formulas had less sphingomyelin than human milk, (a concern, since sphingomyelin is used for producing myelin, which insulates neurons). Free choline concentrations in mature human milk were 30–80% lower than that found in bovine milk or formulas. Mature human milk also has lower free choline than colostrum-transitional human milk. Phosphocholine is particularly abundant in human milk. Overall, formulas, milks, and breast milk appear to provide different amounts and forms of choline, and Holmes-McNary et al. suggests "This may have consequences for the relative balance between use of choline as a methyl donor (via betaine), acetylcholine precursor (via choline), or phospholipid precursor (via phosphocholine and phosphatidylcholine)".^[87] This is supported by Ilcol et al.'s observations that serum free choline concentrations were lower in formula-fed infants than in breast-fed infants.^[76]

More broad interpretations of breast milk consumption versus formula use have also been investigated – though some researchers in the field feel that meta-analysis of the problem should be treated with skepticism, given the multitude of factors that impact cognitive development in humans. Uauy & Peirano, in their editorial for the American Journal of Clinical Nutrition state: "The magnitude of the effect of breast-feeding on IQ is somewhat lower than that of anemia and lead burden. Yet feeding mode is an intervention that affects the whole population, thus, the net effect of improving IQ by 3 points may be similar if not larger than that of gaining 6 points in 5–10% of the children.". Additionally, they go on to summarize that "The burden of proof should be placed on those who propose that feeding formula from a bottle can equal feeding milk from the breast."^[88] There is some science behind this proposal. Lucas et al., after adjusting for social and educational factors on development, still found that preterm children consuming breast milk via tube performed over half a standard deviation higher on IQ tests at 7.5–8 years of age than their cohorts that did not receive breast milk. Previously he had also found an improvement in cognitive development as early as 18 months in preterm infants consuming breast milk versus those not consuming breast milk.^[81]

The argument has been made that the increased IQ and developmental performance exhibited by breastfed infants stems from interaction between the mother and child as well as, or without any additional input from, the actual milk. Drane and Logemann suggest that lactation increases oxytocin and prolactin production, generating feelings of well-being in the mother and encouraging nurturing behavior. This may lead to better mother-child relationships and that may in turn generate improved neural performance.^[89] Additionally, social class and maternal education are highly correlated with type of infant feeding, (formula vs. breastfeeding), while also being correlated to observed cognitive performance. Lucas et al., however, refutes the assumption that fluid breast milk itself has no or minimal beneficial function on cognitive performance later in life. They report an increase in IQ between preterm infants, (and later 7.5–8 yr old children), provided with breast milk and those not provided with breast milk via nasogastric tube, without any interaction between mother and offspring and with controlling for social and educational factors.^[81]

Current consumption levels by lactating and pregnant women

Shaw et al. found that 25% of pregnant women studied in California had observed intakes of less than half the estimated daily choline intake for women.^[90]

Cognitive performance and choline in breast milk

A meta-analysis on breastfeeding and cognitive development indicated that breast feeding was associated with higher scores for cognitive development than formula use. Additionally, the longer the duration of breastfeeding the greater the cognitive developmental benefit in offspring and this benefit was evident early in development and sustained up to 15 years of age, (the last time point at which IQ was measured in the meta-analysis). In addition to IQ performance, breastfed children had more rapid maturation of visual functions and appeared to acquire motor skills at an earlier age. Researchers in the meta-analysis also suggested that breastfed children had fewer emotional or behavioral problems and exhibited fewer minor neurological problems later in life.^[91] As previously stated, choline is necessary for neural development and is higher in breast milk than in formula, and therefore choline may be playing a role in the higher performance of breastfed infants.^[76] However, in the meta-analysis under discussion, the author attributed increased cognitive performance to presence of long-chain polyunsaturated fatty acids (LCPUFAs) such as docosahexaenoic acid and arachidonic acid, which are lipid components within the brain. Docosahexaenoic acid is enriched in phospholipids produced through the PEMT pathway, (previously mentioned as the pathway responsible for de novo choline production). This means that choline production contributes to the body's docosahexaenoic acid pool, and may have implications for docosahexaenoic acid/choline cotransfer into breastmilk. In this meta-analysis they state that the difference between formula and breastfed infants is derived from a lack of these LCPUFAs in infant formulas available in the United States, and no data connecting choline content of the diet and de novo choline production to docosahexaenoic acid has come to light, (data was not provided for formula sources from other countries).^[91] Since choline also plays a role in brain development, and differences in choline are present between breast milk and formula, it seems possible that choline could also be playing a role in observed IQ score improvement in breastfed offspring.

Additional images[link]

• 

  Choline (C5H14NO+)

• 

  Choline chloride

• 

  Choline hydroxide

See also[link]

• Cytidine diphosphate choline
• Dimethylethanolamine

Notes[link]

References[link]

External links[link]

• Choline bound to proteins in the PDB
• Choline, Linus Pauling Institute
• Choline, Kyoto Encyclopedia of Genes and Genomes