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Experimental Gerontology 43 (2008) 378381

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Mini Review

Possible roles of zinc nutriture in the fetal origins of disease

Wolfgang Maret, Harold H. Sandstead

Division of Human Nutrition, Department of Preventive Medicine and Community Health, The University of Texas Medical Branch,
Galveston, TX 77555-1109, USA
Received 12 September 2007; received in revised form 11 October 2007; accepted 15 October 2007
Available online 22 October 2007

Abstract
Risk of diseases of metabolism such as atherosclerosis and adult onset diabetes mellitus is increased by fetal malnutrition. Deciencies
of micronutrients essential for methylation are believed to contribute to the phenomenon in part through epigenetic abnormalities. Zinc
is one of the nutrients essential for the epigenome. Because the worldwide prevalence of zinc deciency is at least 20%, fetal zinc deciency is common. We suggest fetal zinc deciency contributes to the pathogenesis of metabolic diseases in adults. In support of our
thesis, research in experimental models and humans established the essentiality of zinc at all stages of intrauterine and infant life. Experiments in rodents and/or non-human primates found that fetal and/or suckling zinc deciency impairs neuropsychological functions of
progeny and that the eects persist in spite of nutritional rehabilitation. In addition, maternal zinc deciency in mice is reported to impair
immunity of progeny; eects persist in spite of nutritional rehabilitation into the next generation. We suspect that zinc deciency is a far
greater human health problem than is generally recognized.
2007 Elsevier Inc. All rights reserved.
Keywords: Zinc deciency; Fetal malformations; Disease in later life; Epigenetics

Many epidemiological studies found inverse associations between birth weight and risk of atherosclerotic cardiovascular disease, adult onset diabetes mellitus, obesity,
and other abnormal metabolic phenomena in later life
(Barker, 2004). The role of maternal nutrition was claried
by examination of obstetrical and food distribution records
collected during the WW-II Dutch winter famine of 1944-5.
Among the ndings was an increased risk in progeny of
atherosclerotic cardiovascular disease, adult onset diabetes
mellitus, obesity, and schizophrenia (Brown et al., 2000; de
Rooij et al., 2006a,b; Hoek et al., 1998; Neugebauer et al.,
1999; Painter et al., 2007a,b; Painter et al., 2006a,b; Ravelli
et al., 2005; Roseboom et al., 2006; Susser et al., 1998). In
addition adverse eects occurred independent of birth
weight.
The following considers the likelihood that maternal
zinc deciency contributes to increased risk of later disease
in progeny. This issue is important because zinc deciency
*

Corresponding author. Tel.: +1 409 772 4661.

E-mail address: hsandste@utmb.edu (H.H. Sandstead).

0531-5565/$ - see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.exger.2007.10.005

is common, aecting at least 20% of humans (Wuehler

et al., 2005).
Adverse eects of zinc deciency on growth of the
human fetus are known. Low maternal and fetal leukocyte
zinc concentrations, indicators of tissue zinc concentrations, were associated with fetal stunting (Meadows et al.,
1983, 1981). Consistent with these ndings dietary zinc less
than 6.1 mg/d was associated with low birth weight (less
than 2500 g) (Scholl et al., 1993). In addition, fetal growth
and head size were greatly improved by maternal treatment
with zinc and micronutrients when maternal BMI is less
than 26 kg/m2 (Goldenberg et al., 1995).
Experiments in animal models found zinc deciency
early in development aects all tissues (Adeloye and Warkany, 1976; Blamberg et al., 1960; Diamond and Hurley,
1970; Hurley and Shrader, 1972, 1975; Hurley and Swenerton, 1966; Kienholz et al., 1961; Warkany and Petering,
1972, 1973). Severe zinc deciency (<1.0 ppm) during suckling causes microscopic teratology in the cerebellum
(Dvergsten, 1984; Dvergsten et al., 1983, 1984a,b). In addition, severe maternal zinc deprivation of rats during the

W. Maret, H.H. Sandstead / Experimental Gerontology 43 (2008) 378381

last third of gestation or throughout lactation causes

abnormal neuropsychological performance in nutritionally
rehabilitated progeny in later life. Manifestations include
poor maze acquisition, poor avoidance conditioning,
decreased short and long term memory, and increased
aggression (Halas and Eberhardt, 1987; Sandstead, 1985).
Additionally, relatively mild maternal zinc deprivation
(10 ppm), throughout gestation and lactation causes residual learning and memory decits in progeny that are evident after more than 100 days of nutritional
rehabilitation (Halas et al., 1986), and microscopic hyperstaining of hippocampal neurons that is evident more than
200 days of nutritional rehabilitation (Hunt, 1984). In
addition, maternal zinc deciency in mice suppresses
immunity in progeny that is reported to persist after nutritional rehabilitation into the next generation (Beach et al.,
1983). As far as we are aware animal experiments have not
addressed the issue of risks of atherosclerosis, adult onset
diabetes mellitus and other diseases.
It has been suggested that eects of malnutrition on the
epigenome might account for increased risks of later disease. Zinc is one of the micronutrients essential for the epigenome. Most relevant is the emerging knowledge about
the involvement of zinc in pathways for generating and
controlling methylation equivalents, as well as in the structures of enzymes that epigenetically modify DNA and histones. DNA methyltransferases, some histone lysine
methyltransferases, and histone deacetylases are all zinc
enzymes (Fatemi et al., 2001; Finnin et al., 2001; Somoza
et al., 2004; Zhang et al., 2002). Consistent with the above,
Zn deciency in rats signicantly decreased methylation of
DNA and histone methylation in isolated perfused rat liver
(Wallwork and Duerre, 1985).
Studies using methyl supplements and zinc adequate
diets (Wol et al., 1998) constitute the rst report of an
eect of dietary methyl supplements on gene imprinting
and specic gene expression, demonstrating that the diet
inuences mechanisms of epigenetic regulation, imprinting,
and development. (Waterland and Jirtle, 2003). The investigators found that supplementation of the maternal diets
with choline, folic acid, vitamin B12, methionine, and zinc
epigenetically modied the expression of the agouti gene in
the ospring, thus showing a relationship between the epigenetic eect and the methionine cycle/transsulfuration
pathway. They suggest that dietary supplementation, long
presumed to be purely benecial, may have unintended deleterious inuences on the establishment of epigenetic gene
regulation in humans. These data clearly suggest that
intrauterine and postnatal environment with regard to
the above micronutrients aects phenotypic outcome in
adulthood.
The methionine cycle/transsulfuration pathway is particularly sensitive to deciencies of folate, pyridoxine, riboavin, vitamin B12, choline/betaine, and methionine,
rendering methylation reactions especially vulnerable to
multi-micronutrient deciencies, which are common in naturally occurring human malnutrition. What could not have

379

been appreciated, however, until recently is the requirement

for zinc in this pathway. Zinc is involved as a catalytic metal
ion for certain enzymes, as a structural metal ion for certain transcription factors, and as a zinc/ATP cofactor for
certain kinases. Betaine-homocysteine methyltransferase
is a zinc enzyme, and based on homology, methionine synthase is also believed to be a zinc enzyme (Evans et al.,
2002). Both enzymes synthesize methionine from homocysteine and are critical in providing S-adenosylmethionine
for methylation reactions. If these enzymes are indeed
aected by zinc deciency as suggested already for methionine synthase (Hong et al., 2000), then zinc deciency
should elicit adverse eects that resemble some of the
abnormalities associated with folate deciency. For example, both zinc and folate deciencies can cause teratology
and cognitive dysfunction.
At the transcriptional level, cystathionine b-synthase,
which makes cystathionine from homocysteine in the transsulfuration pathway is under control of Sp1, a zinc-dependent transcription factor, and other zinc-dependent
transcription factors (Ge et al., 2001). The transcription
of serine hydroxymethyltransferase is regulated by zinc
through Sp1 and MTF-1, both zinc-dependent transcription factors, indicating a regulatory eect of zinc on folate
metabolism (Perry et al., 2005). This enzyme serves as a
switch that directs the ow of folate-activated one-carbon
units from remethylation to thymidylate synthesis and catalyzes one of the reactions that introduce new methyl
equivalents from serine into the methionine cycle.
Pyridoxal kinase and riboavin kinase (McCormick,
2002) prefer a zinc/ATP complex over the typical Mg/
ATP as their substrate. The interactions of these enzymes
with the zinc/ATP complex have now been established by
X-ray crystallography (Bauer et al., 2003; Li et al., 2002).
FMN is essential for pyridoxine/pyridoxal interconversion. Pyridoxal phosphate is the coenzyme for the formation of 5,10-methylenetetrahydrofolate and in the
cystathionine b-synthase reaction. FAD is essential for
transformation of 5,10-methylenetetrahydrofolate to
5-methylenetetrahydrofolate.
In conclusion, zinc is essential for all stages of early
development. Deciency can cause residual abnormalities
of function. At a biochemical level several pathways relevant for epigenetic mechanisms require zinc. Thus it seems
likely that zinc nutriture, through function of the epigenome, aects risk in humans of diseases of metabolism
later in life. If this is true, low zinc nutriture is a far greater
health problem than has been recognized.
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