Importance of Choline as Essential Nutrient and Its Role in Prevention of Various Toxicities

Abstract

Choline is a water-soluble essential nutrient included as a member of the vitamin B12 group owing to its structural similarities with that of the other members of the group. Its roles and functions, however, extend much wider than that of the vitamins with which it is grouped. Choline is vital for maintenance of various key metabolic processes which play a role in the prevention or progression of various health impairments. The occurrence of diseases like neural tube defect (NTD) and Alzheimer's is prevented by the metabolic role of choline. It is also indispensable for mitigation of various forms of toxic contamination. While adequate level of choline in the body is essential, an excess of choline can result in various forms of disorder. To maintain the optimal level of choline in the body can be a challenge. The vital roles played by choline together with the range of contradictions and problems that choline presents make choline an interesting area of study. This paper attempts to summarize and review some recent publications on choline that have opened up new prospect in understanding the multiple role played by choline and in throwing light on the role played by this wonder essential nutrient in mitigating various forms of toxic contamination.

Full text

Choline and Its Role against Toxicities
Prague Medical Report / Vol. 116 (2015) No. 1, p. 5–15
5)
Importance of Choline as Essential
Nutrient and Its Role in Prevention
of Various Toxicities
Somava Biswas, Sarbani Giri
Department of Life Science and Bioinformatics, Assam University, Silchar, India
Received November 2, 201 4; Accepted March 1 2, 201 5.
Key words: Choline – DNA repair – Fetotoxicity – Neurotoxicity – Neural tube
defect – Antioxidant
Abstract: Choline is a water-soluble essential nutrient included as a member of
the vitamin B12 group owing to its structural similarities with that of the other
members of the group. Its roles and functions, however, extend much wider than
that of the vitamins with which it is grouped. Choline is vital for maintenance of
various key metabolic processes which play a role in the prevention or progression
of various health impairments. The occurrence of diseases like neural tube defect
(NTD) and Alzheimer’s is prevented by the metabolic role of choline. It is also
indispensable for mitigation of various forms of toxic contamination. While
adequate level of choline in the body is essential, an excess of choline can result
in various forms of disorder. To maintain the optimal level of choline in the body
can be a challenge. The vital roles played by choline together with the range of
contradictions and problems that choline presents make choline an interesting area
of study. This paper attempts to summarize and review some recent publications
on choline that have opened up new prospect in understanding the multiple role
played by choline and in throwing light on the role played by this wonder essential
nutrient in mitigating various forms of toxic contamination.
http://dx.doi.org/10.14712/23362936.2015.40
© Charles University in Prague – Karolinum Press, 2015
Mailing Address: Prof. Sarbani Giri, Department of Life Science and Bio-
informatics, Assam University, Silchar-788011, India; e-mail: girisarbani@yahoo.com

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Introduction
Choline (trimethyl-beta-hydroxyethylammonium) (Figure 1) is a dietary component
that is crucial for normal functioning of all cells (Zeisel and Blusztajn, 1994). It
was discovered by Andreas Strecker in 1862, but was ofcially recognized as an
essential nutrient by the US Institute of Medicine’s Food and Nutrition Board
(Food and Nutrition Board, 1998). Choline is a quaternary ammonium compound
that lacks ester bond and contains three methyl groups which are a vital
requirement for an array of metabolic reactions.
Though choline has often been clubbed with vitamin B12 group, its functions
however, suggest that it is more than just another vitamin. Choline in the diet
is available as free choline or is bound as esters such as phosphocholine (Pho),
glycerophosphocholine (GPCho), sphingomyelin (SM) or phosphatidylcholine
(PtdCho). From these choline esters, choline is freed by pancreatic enzymes.
Dietary choline from a variety of choline containing foods is absorbed by the
intestine and uptake is mediated by choline transporters. The fate of choline is
conversion into PtdCho (also known as lecithin), which occurs in all nucleated
cells (Li and Vance, 2008). PtdCho is the predominant phospholipid (>50%)
in most mammalian membranes (Zeisel, 2006a). Choline is absorbed in small
intestine. Free choline enters the portal circulation and is mostly taken up by the
liver (Le Kim and Betzing, 1976). Lipid soluble PtdCho and SM enter via lymph
and bypass the liver. Therefore, different forms of choline could have different
bioavailability (Cheng et al., 1996). Betaine, a choline derivative, plays an important
role in donation of methyl groups to homocysteine to form the essential amino
acid methionine (Zeisel et al., 2003). Choline uptake by liver, kidney, mammary
gland, placenta and brain is of special importance. Choline and choline containing
compounds are crucial for normal sustenance of life. Choline or its metabolites
are important for the structural integrity of cell membranes, methyl-metabolism,
transmembrane signalling, lipid and cholesterol transport, metabolism and
cholinergic neurotransmission and therefore it is vital during critical periods in
brain development.
Choline was added to the list of essential nutrients only in recently. In 1998,
based on the contemporary research studies, the US Institute of Medicine’s Food
and Nutrition Board, recognized that for the maintenance of normal health,
OH
N
+
H
3
C
H
3
C
CH
3
Figure 1 – Chemical structure of choline.

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humans needed to obtain choline from the diet and issued guidelines for its
daily intake. Choline is found in a wide variety of foods, mainly in the form of
phosphatidylcholine, which is often called lecithin. Among the most concentrated
sources of dietary choline are egg yolk and offal, beef, nuts, leafy greens, legumes,
seed oils, grain germs, and dairy products (Shronts, 1997). However, choline can
also be synthesized de novo.
The liver is the primary site for endogenous synthesis of choline. The only
other source of choline apart from normal diet is from the de novo biosynthesis
of phosphatidylcholine (PtdCho). Phosphatidylethanolamine N-methyltransferase
(PEMT) activity catalyses the synthesis of PtdCho by the sequential methylation
of phosphatidylethanolamine (PtdEtn), using S-adenosylmethionine (AdoMet) as
a methyl donor and forms a new choline moiety (Blusztajn et al., 1985).
Several factors such as gender, menopausal status, pregnancy, lactation and
genetic mutation affect choline requirement of an individual and de novo synthesis
of choline alone fails to meet all human requirements for choline; as a result the
recommended adequate intake (AI) for choline has been set at 425 mg/day for
women, 450 mg/day for pregnant women, 550 mg/day for men and lactating women
as well (Food and Nutrition Board, 1998).
Choline requirement is diminished in premenopausal women because estrogen
induces PEMT (Resseguie et al., 2007), the gene in liver enabling endogenous
biosynthesis of choline moiety. But many women have single nucleotide
polymorphism (SNPs) in the PEMT gene that repeals estrogen-induction of
endogenous synthesis (Resseguie et al., 2011) and these women, therefore, require
dietary choline just as men do. Thus genetic variance can have effects on choline
requirement. Notably, the adequate intake of choline is increased for pregnant and
breastfeeding women to satisfy the needs of the fetus and the baby whose choline
is supplied via placenta and milk (Zeisel et al., 1986). Also, many of the foods that
have high choline content are also high in fats or cholesterol (e.g. eggs). As a result,
many people are decreasing their intake of these foods leading to a situation where
only a few people today adhere to a diet that meets the recommended choline
levels (Food and Nutrition Board, 1998; Jensen et al., 2007).
The reasons mentioned above have resulted in an increasing population with
a choline decient diet which ultimately impedes many normal physiological
processes as well as causes a diverse group of pathological processes. In most
mammals, prolonged (weeks to months) ingestion of a diet decient in choline
leads to consequences that include hepatic, renal, pancreatic, memory and growth
disorders.
However, excess choline intake has detrimental effect in human too. Choline
doses that are of magnitude greater than estimated intake from food have been
associated with body odor, sweating, salivation, vomiting, gastrointestinal effects,
hypotension and hepatotoxicity in humans (LSRO/FASEB, 1981). These apparently
contradictory facts about choline, makes its maintenance in the body a challenge.

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In view of the importance of choline as a nutrient it is of utmost importance
to review the protective action of choline against genotoxicity, neurotoxicity,
fetotoxicity and antioxidative potentials. This review summarizes some current
literature ndings on the effects of choline in mitigating various toxicity targeting
DNA and repair system, neurons, development and fetotoxicity.
Methodology of literature sources selection
The Tables in this review contain the summary of original research articles, case-
control and cohort or cross sectional studies published between 2003 and 2013.
A literature search was undertaken using Science Direct, PubMed and Google
using specic key words. Title and abstracts were read and inclusion/exclusion
being decided according to the key words which included choline along with
toxicity, genotoxicity, DNA, DNA damage, apoptosis, teratogenicity, maternal
health, fetal alcohol syndrome, pregnancy, antioxidant properties, neurotoxicity,
neural tube defect, neuroprotection. All the abstracts were read to decide on the
inclusion criteria. Studies were included based on the following parameters: i) if
the focus was on relevant outcomes i.e. role of choline in mitigating genotoxicity,
neurotoxicity, fetotoxicity and antioxidative potentials etc., ii) if the articles were
in English.
Studies were excluded if: i) only abstract was available, ii) primary emphasis were
on other one carbon nutrients like folate, vitamin B6, vitamin B12, methionine
and betaine, iii) focus laid on role of choline in methionine formation via folate
metabolism.
Review
Choline: its role in DNA damage and repair
Choline deciency has been associated with DNA damage (Table 1). DNA
methylation is inuenced by choline that ultimately inuences genomic stability
(Loughery et al., 2011) by altering gene expression for critical genes involved
in DNA mismatch repair, resulting in increased mutation rates. Steven H. Zeisel
(2012) summarized that choline deciency increases leakage of reactive oxygen
species from mitochondria which is due to altered mitochondrial membrane
composition and enhanced fatty acid oxidation. Choline deciency impairs folate
metabolism since the metabolic pathways of these two have a closely knit pathway
of metabolism, resulting in decreased thymidylate synthesis and increased uracil
misincorporation into DNA, with strand breaks resulting during error-prone repair
attempts.
Choline and neurotoxicity
A number of researches conducted since 1980s have proved that choline
accelerates the synthesis and release of acetylcholine in nerve cells, which is one of
the principal neurotransmitters (Haubrich et al., 1974; Cohen and Wurtman, 1975;

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Table 1 – Some recent research publications showing choline deciency
association with DNA repair in various test systems
Sl. no. Test system Observed effects References
1. Rats Oxidative damage to DNA by formation of apurinic/
apyrimidinic sites and Ogg1-sensitive sites in DNA
build up due to choline deprivation.
Powell et al.
(2005)
2. Human Choline deciency in humans is associated
with signicant damage to DNA and with apoptosis
in peripheral lymphocytes.
da Costa
et al. (2006)
3. Male Sprague-
Dawley rats
Choline is an important methyl donor and is involved
in more than 150 one-carbon transfer reactions
including DNA repair and DNA methylation.
Shinohara
et al. (2006)
4. In vivo (male
weaning Fisher
344 (F344) rats)
Choline deciency is correlated with the silencing
of several tumor suppressor genes responsible
for DNA repair.
Pogribny et al.
(2009)
5. In ovo (chicken
DT40 model
system)
Choline inuences histone methylation,
which in turn is important for the activation
of DNA damage response pathways that consist
of complex signalling networks that detect
and repair DNA damage before the cell divides.
FitzGerald
et al. (2011)
Wecker, 1986; Zeisel, 2006a). From diminishing memory loss to preventing neural
tube defects, which are a group of congenital malformations, choline plays a crucial
role in combating neurotoxicity (Table 2). Though the etiology of Alzheimer’s
disease is unknown, postmortem studies of brain samples from Alzheimer’s disease
patients showed lower levels of acetylcholine (Nitsch et al., 1992). In a review,
Zeisel (2006b) observes that dietary intake of choline by a pregnant mother and
later by the infant directly inuences brain development and results in permanent
changes in brain function including memory enhancement and learning functions.
Experiments with animal models testify that choline supplementation during
neonatal period prevents memory decline due to age (Meck and Williams, 2003)
and decreases apoptosis rate in hippocampus of fetus whose mothers consumed
high choline diets (Craciunescu et al., 2003). In a review Ziesel and da Costa
(2009) highlights recent studies which show that choline supplementation during
critical periods of neonatal development can have long-term benecial effects on
memory. The mechanism whereby choline supplementation in mothers results in
a permanent change in memory of their offspring is not clear. It was assumed that
increased brain choline results in subsequent increase in acetylcholine release.
However, further investigations proved that choline supplementation to dams
results in signicantly greater accumulation of phosphocholine and betaine in fetal
brain as compared to fetuses without choline exposure (Garner et al., 1995).
Although there are sufcient data with animal models indicating that choline is a

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Table 2 – Some recent articles showing choline deciency association
with neuronal development in various test systems
Sl. no. Test system Observed effects References
1. In vivo (mice
model)
Improvement of the memory and cognitive
dysfunction in Alzheimer’s disease are observed
on choline acetyltransferase supplementation.
Fu et al.
(2004)
2. Sprague-Dawley
albino rats
Choline supplementation during critical period of
fetal development alters brain morphology including
structure and function of hippocampal pyramidal
cells, larger soma size and increase in number
of primary and secondary dendritic branches.
Li et al.
(2004)
3. Human female
(population based
case control study)
Decient maternal dietary intake of choline during
pregnancy in humans may lead to an increased risk
of having a baby with a neural tube defect.
Shaw et al.
(2004)
4. Female Sprague-
Dawley rats
Sensory inhibition gets reduced with gestational
choline deciency.
Stevens
et al. (2008)
5. In ovo (chick
embryo)
Choline at low dose (25 µg/µl) protected against
sodium-arsenite induced NTDs in chick embryos by
reversed DNA hypomethylation and cell apoptosis.
Song et al.
(2012)
6. Female rats Supplemental dietary choline, when received during
development, has anxiolytic effects and may inoculate
an individual against stress and psychological
disorders like depression.
Glenn et al.
(2012)
necessary nutrient in reducing cognitive decline and it aids in brain hippocampal
development and that choline supplementation during pregnancy results in multiple
modications in the patterns of gene expression known to inuence learning and
memory, yet there are insufcient human studies to conrm the same (Mellott et
al., 2007). Also, several studies hypothesize that choline may play the protective role
against neural tube defects (NTDS) by contributing methyl groups through betaine
and lowering homocysteine concentration.
Choline and teratogenicity/fetotoxicity
Maternal nutrition is important for normal human development and in particular
the supply of methyl groups is vital at all stages from conception to early infancy.
Adequate maternal choline intake is vital to a healthy pregnancy. A number of
studies have demonstrated the protective role of maternal choline supplementation
(Table 3). Maternal choline intake is critical not only for proper fetal brain
development, but also for maintaining normal maternal homocysteine levels.
Elevated maternal homocysteine has been associated with an increased incidence
of birth defects, such as neural tube defect, spontaneous abortions and low birth
weight babies.

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Table 3 – Some research articles showing association of choline
with developmental disorder mitigation in various test systems
Sl. no. Test system/
Subjects
Observed effects References
1. Population based
control study
in human
Periconceptional intake of choline may contribute
to reduced risk of orofacial clefts.
Shaw et al.
(2006)
2. Sprague-Dawley
rats
Choline availability during pregnancy has an enduring
impact on hippocampal neurogenesis of the offspring
i.e. prenatally choline supplemented animals showed
increased adult neurogenesis.
Glenn et al.
(2007)
3. Mouse models Prenatal or postnatal choline supplementation
attenuates the motor coordination decits
and improves neuronal integrity, proliferation
and survival in Rett syndrome.
Nag et al.
(2008), Ward
et al. (2009)
4. In vivo (Sprague-
Dawley rats)
Nutritional supplementation with choline in rats
exposed to ethanol in utero almost completely
mitigates the degenerative effects of ethanol on
development and behavior. Further, the therapeutic
window of choline, being quite large, can effectively
attenuate ethanol’s teratogenic effects whether
administered during prenatal ethanol exposure
or after the alcohol insult is complete.
Thomas et al.
(2009, 2010)
5. Human Supplementation of choline to mothers may mitigate
the effects of the alcohol and reduce the severity
or prevalence of FAS.
Ballard et al.
(2012)
Choline as antioxidant
An undisturbed choline transport and distribution throughout the body essentially
plays a vital role in multiple clinical manifestations. The methyl donation function of
choline is of major importance in maintaining balanced cellular antioxidant defence
systems thereby checking oxidative stress and apoptosis (Table 4). A recent review
(Corbin and Zeisel, 2012) sites a battery of works which attempts to establish the
intricate connection between choline deciency and development of non-alcoholic
fatty liver disease (NAFLD) which may ultimately progress to hepatocarcinogenesis.
Studies in human as well as in mouse, conrm that a deletion of choline-related
genes, alteration of mitochondrial membrane composition owing to choline
deciency, chronic endoplasmic reticulum stress, levels of gut microbiome
modulating the availability of choline may enhance the fatty liver disease.
Discussion and Conclusion
The recognition to choline as an essential nutrient is not a new concept. In the
past choline has been recognized as an essential nutrient as being biologically

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Table 4 – List of some recent studies on antioxidative role of choline
Sl. no. Test system/
Subjects
Observed effects References
1. Weanling Wistar
male rats
Choline deciency produces oxidative damage in the
liver, heart, kidney, and brain, with an increased lipid
peroxidation of subcellular organelles and a decrease
in tissue antioxidants.
Ossani et al.
(2007)
2. Male Fisher
344 rats
Chronic methyl group deciency due to low levels
of dietary choline leads to an imbalance in cellular
antioxidant defence systems, increased oxidative
stress, and apoptosis.
Bagnyukova
et al. (2008)
3. Male Swiss
mice
Folate deprivation and radiation interact to mobilize
additional choline reserves of hepatic tissue for
redistribution to other organs, which could not be
utilized by folate deciency alone and thereafter
trigger utilization of choline as substitute for selected
one-carbon transfer reactions.
Batra et al.
(2009)
4. Weanling male
Wistar rats
Decreased antioxidant content and increased lipid
peroxidation are earlier biochemical alterations that
precede and lead to histological cell death by necrosis
in choline deciency.
Repetto et al.
(2010)
5. Rodent model
(C57BL/6J wild-
type mice)
Adverse effects of choline deciency on hepatic
mitochondrial structure and function could be linked
to the unique signature of hepatic lipid accumulation,
inammation, and cellular and mitochondrial injury
induced in mice maintained on a very high fat,
protein-restricted, very low carbohydrate and
ketogenic diet.
Schugar et al.
(2013)
important, without a complete understanding about the underlying reasons. The
earlier recognition was not backed up by studied evidence about its precise
functions in the various complex biological processes. But there is a vital difference
in the approach to the recognition following newer ndings. The recent studies
provide a clear insight into the molecular basis of various roles played by choline
and its metabolites, leading to better understanding about the functions of
these substances in health and disease development and control processes. This
understanding based on the recent ndings establishes choline as a vital component
of our diet requirement and opens up newer areas of knowledge, ways in which
many physiological conditions take place and the role played by choline in these
processes. The understanding offers a clue into the mechanisms associated with
diseases like Alzheimer’s, non-alcoholic fatty liver disease, fetal alcohol syndrome
and neural tube defects with the prospect to control, minimize and even to cure
them.

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