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Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160-7421
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • knockout • mice • metallothionein • pregnancy • zinc deficiency
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). A deficiency of this essential metal results in a wide
spectrum of physiological effects, including disorders of the skin and
neurological, immune and reproductive systems (Apgar 1985
, Walsh et al. 1994
). These effects reflect
the diverse functions of zinc. Zinc is required for the activity of
many enzymes and DNA-binding proteins (Vallee and Falchuk 1993
, Walsh et al. 1994
). Zinc may also modulate
the activity of peptide hormones (e.g., insulin-like growth
factor-I and growth hormone) and neurotransmitter receptors
(Vallee and Falchuk 1993
). Moreover, zinc can exert
antioxidant activity by protecting sulfhydryl groups and stabilizing
cell membranes, and it may modulate the cell cycle and the process of
apoptosis (Prasad 1998a
, Rogers et al. 1995
). In addition, zinc deficiency was correlated with iron
and vitamin A deficiencies (Lönnerdal 1998
,
Prasad 1998a
).
Zinc deficiency profoundly effects reproductive processes
(Vallee and Falchuk 1993
, Walsh et al. 1994
). Abnormal gametogenesis and reduced secretion of
gonadotropins were reported (Apgar 1985
). Zinc
requirements increase during the latter half of pregnancy, coincident
with the rapid growth and morphogenesis of the embryo (Walsh et al. 1994
), and embryonic development and morphogenesis are
jeopardized by zinc deficiency (Apgar 1985
). In humans,
zinc supplementation during pregnancy increases the birth weight and
head circumference of newborn infants (Lönnerdal 1998
). In rats, zinc deficiency during the pre-implantation
period adversely alters blastocyst morphology and reduces the
implantation success rate (Vallee and Falchuk 1993
),
whereas exposure to zinc deficiency during the postimplantation period
can be embryotoxic. Embryos in zinc-deficient dams show a high
incidence of teratogenesis, such as craniofacial and limb bud
abnormalities and growth retardation (Apgar 1985
). In
mice, zinc deficiency during pregnancy can be teratogenic and/or
embryotoxic, but apparently has little effect on pre-implantation
development in vivo (Dalton et al. 1996
).
Zinc metabolism is controlled by uptake, storage in peripheral tissues,
and secretion, but the mechanisms regulating homeostasis of this metal
are poorly defined. Zinc absorption occurs in the intestinal mucosa
(Oestreicher and Cousins, 1989
), but under normal
conditions, nearly as much zinc is lost in the bile-pancreatic
secretions as is absorbed by the intestine (McClain 1990
, Walsh et al. 1994
). Dietary zinc
availability influences uptake and efflux of zinc. Excess zinc leads to
reduced absorption, whereas uptake increases during periods of zinc
deficiency and during pregnancy (Walsh et al. 1994
).
Several mammalian genes involved in zinc transport were recently
identified (Eide 1997
, McMahon and Cousins 1998a
). These genes encode membrane spanning proteins
(zinc-transporters 1–4;
ZnT3
) that function in the transport, efflux or vesicular storage of zinc
(Palmiter et al. 1996a
and b
). For example, ZnT-1 functions to
efflux zinc from cells (Palmiter and Findley 1995
), and
its expression in the intestine is influenced by dietary zinc intake
(McMahon and Cousins 1998b
). A point mutation in ZnT-4
causes lethal mouse (lm) syndrome (Huang and Gitschier 1997
) in which newborn pups nursed by lm mothers fail to
survive to weaning because of a lack of zinc in the milk. Recent
studies on yeast and Arabidopsis have identified the ZIP
gene family of membrane-spanning, zinc transporters, which function
in the uptake of zinc from the surrounding environment, and whose
expression is regulated in response to changing zinc availability
(Eide 1997
). Homologues of the ZIP gene family were
identified in humans and mice (Eng et al. 1998
).
Although the functional importance of the mammalian ZIP genes has not
been determined, it is clear that zinc transporter genes (ZnT and ZIP)
play a central physiological role in zinc homeostasis.
One potential mechanism for the storage of zinc in tissues are the
metallothioneins (MT). MT are the most abundant intracellular,
zinc-binding proteins, and they are isolated from tissues primarily
complexed with seven atoms of zinc per molecule of MT (Andrews 1990
). In the mouse, four MT genes have been cloned (MT-I
through -IV) (Palmiter et al. 1993b
), but the MT-I
and MT-II genes are expressed in many cell types, and the
transcription of those genes is regulated by free zinc concentrations
in the cell. In contrast, the MT-III and MT-IV genes are not
regulated by metal ions. Expression of the MT-I gene in response to
zinc involves the zinc-finger transcription factor MTF-1
(Heuchel et al. 1994
). MTF-1 is a metalloregulatory
protein whose DNA-binding activity is apparently activated in
response to increased free zinc concentrations in the cell
(Bittel et al. 1998
, Dalton et al. 1997
).
When free zinc levels increase, the cell responds by increased
synthesis of MT, which in turn chelates the free zinc. Reciprocally, if
zinc levels decline, the synthesis of MT and steady-state levels of
MT are diminished, and the amount of zinc bound in the MT pool is
decreased. Furthermore, the bioavailability of zinc bound to MT may be
influenced by the redox status of the cell (reviewed by Palmiter 1998
).
These findings suggest that the MT-I and MT-II genes play a
role in zinc homeostasis (Bremner 1991
, Cousins 1985
). However, genetic studies demonstrate that the MT-I
and-II genes are not essential, thus the functions of MT remain elusive
(Palmiter 1998
). A possible physiological function of MT
during pregnancy is suggested indirectly by the finding that the mouse
MT-I and MT-II genes are actively expressed in cells that
surround the developing embryo (visceral yolk sac, placenta,
deciduum) (Andrews 1990
, Andrews et al. 1993
). More direct evidence for this role of MT was
obtained by the analysis of transgenic mice that over-express MT
(Palmiter et al. 1993a
) or that have loss-of-function
mutations (gene KO) of the MT-I/II genes (Masters et al. 1994
). Transgenic mice that over-express MT-I accumulate
more zinc in maternal organs and are significantly more resistant to
the teratogenic effects of dietary zinc deficiency during pregnancy
than are control mice (Dalton et al. 1996
), and dietary
zinc deficiency during the neonatal period causes abnormal development
of the kidney in the MT-I/II KO mice, but not in control mice
(Kelly et al. 1996
). Thus, a physiological function of
the MT-I and -II genes may be to help protect against the stress of
dietary zinc deficiency. To further examine the roles of MT in zinc
homeostasis, particularly during pregnancy, we determined the relative
sensitivity of MT-I/II KO mice to the teratogenic and embryotoxic
effects of dietary zinc deficiency. In addition, we determined the
relationship between the embryonic MT genotype and sensitivity to
dietary zinc deficiency. The results of these studies suggest that
maternal as well as embryonic MT gene expression is reproductively
advantageous.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All experiments involving animals were conducted in accordance with NIH
guidelines for the care and use of experimental animals, and
all animal experiments were approved by our Institutional Animal Care
and Use Committee. Mice homozygous for targeted disruption of the
MT-I and MT-II genes (Masters et al. 1994
) were
purchased from Jackson Laboratories (Bar Harbor, ME). These mice were
of the 129/SvCPJ genetic background. Because of the poor reproductive
success (high spontaneous embryo resorption rate) of this strain of
mice, we outbred the MT-I/II KO mice to CD-1 females (48–60 d old;
Charles River Breeding Laboratories, Raleigh, NC) for three
generations. The heterozygous MT-I/II KO (+/-) mice obtained were then
inbred to yield homozygous MT-I/II KO (-/-) mice and nontransgenic
control (+/+) littermates. Those mice were then inbred to create
working colonies of animals, and age matched mice of each strain were
compared. As indicated below, in some experiments, heterozygous MT-I/II
KO (+/-) males were bred to nontransgenic control females or homozygous
MT-I/II KO females.
Mouse diets were purchased from Harlan Teklad (Madison, WI) and have
been described in detail previously (Dalton et al. 1996
). Zinc levels in the diets were as follows:
Zinc-deficient (Zn-D), 0.5–1.5 µg/g or 2.5–5 µg/g (as
indicated); zinc-adequate (Zn-A), 50 µg/g. Each of these diets
contained ~18 µg/g Cu, and were otherwise identical. Food intake
was monitored in all experiments, and it did not differ between groups
of mice fed the Zn-D compared with those fed the Zn-A diet.
Experimental designs.
Experiment 1.
To determine MT levels in maternal tissues and in the conceptus of
control and MT-I/II KO mice, homozygous MT-I/II KO female mice and
control female mice were mated with homozygous MT-I/II KO or control
male mice. On day 1 (vaginal plug) of pregnancy, mice were placed in
pairs in cages with stainless steel false bottoms to reduce recycling
of zinc (Cook Mills and Fraker 1993
). Mice were provided
free access to the Zn-A feed and deionized, distilled water. Water
bottles were washed in 4 mol/L HCl and rinsed in deionized water to
remove zinc (Cook Mills and Fraker 1993
). To measure
maternal and embryonic MT levels, on day 14 of pregnancy, the pancreas
visceral yolk sacs, placentae and embryos were collected from the mice
fed the Zn-A. Maternal tissue samples were pooled from 3 to 6
females, and embryos and extra-embryonic tissues were pooled from
6 implantation sites for each group. Samples were frozen in nitrogen
and later assayed in sextuplet for Cd-binding activity. This
experiment was repeated twice. Inbreeding of the MT-I/II KO mice and of
the control mice yielded embryos of the -/- or +/+ MT-I/II genotypes,
respectively. Cross-breeding of MT-I/II KO females and control
males or visa versa yielded embryos of the +/- genotype.
Experiment 2. To examine the effects of severe dietary zinc deficiency on pregnancy, homozygous MT-I/II KO female mice and control female mice were mated with CD-1 male mice. On d 1 of pregnancy, mice were housed three per cage on cedar bedding, and allowed free access to the Zn-A or the Zn-D (1 µg/g) feed and deionized, distilled water. To assess effects on pregnancy, mice were maintained under these experimental conditions until d 14, at which time the pregnancy rate, the total number of implantation sites and the number of resorbed and nonresorbed implantation sites per uterus were determined visually, and the morphology of nonresorbed fetuses was determined by examination under a dissecting microscope.
Experiment 3. To examine the effects of moderate dietary zinc deficiency on pregnancy, homozygous MT-I/II KO female mice and control female mice were mated with CD-1 male mice. On d1 (vaginal plug) of pregnancy mice were placed in pairs in cages with stainless steel false bottoms as in expt. 1. Beginning on d1 mice were allowed free access to the Zn-A or the Zn-D (5 µg/g) feed and deionized-distilled water. To assess effects on pregnancy, mice were maintained under these experimental conditions until d 14 at which time the pregnancy rate, the total number of implantation sites and the number of resorbed and nonresorbed implantation sites per uterus were determined visually, and the morphology of nonresorbed fetuses was determined by examination under a dissecting microscope.
Experiment 4. To further examine the effects of moderate dietary zinc deficiency on pregnancy, an experimental design identical to expt. 3 was employed, except that pregnant mice were allowed free access to the Zn-A diet until day 8 of pregnancy, at which time the diet was changed to the Zn-D (1 µg/g) diet, or the mice were maintained on the Zn-A diet. The effects on pregnancy were determined on day 14, as described above.
Experiment 5. To examine the influence of embryonic genotype on sensitivity to zinc deficiency during pregnancy, homozygous MT-I/II KO female mice and control female mice were mated with heterozygous MT-I/II KO male mice and then manipulated as in expt. 4. At day 14, morphologically abnormal embryos were collected, and the MT genotype determined by polymerase chain reaction (PCR) as described below.
Cadmium-hemoglobin exchange assay for MT (Cd-binding proteins).
Steady state levels of total MT were measured by using the
cadmium-hemoglobin exchange assay (Eaton and Cherian 1991
).
Genotyping of fetuses by PCR.
DNA was prepared from individual embryos, and the normal and disrupted
MT-I gene was amplified by PCR and was distinguished by cleavage of
the PCR product with KpnI. Primers and reaction conditions were
as described (Masters et al. 1994
).
Statistical analysis.
Statistical significance was determined by using ANOVA and Z-test and Chi square analysis. Differences were considered significant when the P-value was <0.05. Values are given as mean ± SD. P-values are presented in the tables.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the homozygous MT-I/II KO mice and nontransgenic control mice on the CD-1 background, the litter sizes averaged 11 pups, and at mid-gestation ~5% of the embryos on average were resorbed under normal conditions. Furthermore, morphologically abnormal embryos were not detected among the >500 embryos examined at day 14 of gestation.
These MT-I/II KO mice had low MT levels in the major organs and in the
conceptus (Table 1
). In nontransgenic control mice, MT levels were highest in the maternal
pancreas and embryonic visceral yolk sac as predicted (Andrews 1990
, Andrews et al. 1993
, Dalton et al. 1996
). In the MT-I/II KO mice, in contrast, the
cadmium-binding activity in heat-stable cytosols from these
organs was reduced to a level of 20 to 11% of those found in the
control mice. MT levels in the placenta and embryo were also reduced
drastically in the MT-I/II KO mice relative to control mice, and
placentae and embryos with heterozygous disruption of the MT-I/II genes
contained intermediate amounts of MT relative to homozygous
conceptuses. In contrast, MT levels in the visceral yolk sac remained
at control levels in the heterozygotes.
|
). MT-I/II gene disruption correlates with increased sensitivity to the effects of dietary zinc deficiency during pregnancy (expts. 2, 3 and 4).
Several different experimental conditions of dietary zinc deficiency during pregnancy were examined. Each condition resulted in different severities of teratogenic and embryotoxic effects measured at day 14.
Pregnant females were fed the zinc-deficient (1 µg/g) diet on day
1, but were housed in cages without false bottoms, which allows for the
recycling of zinc (expt. 2). The pregnancy rate and implantation
success were not affected by this acute zinc deficiency in either
strain of mice (Table 2
). In sharp contrast to this, fetal development was severely impaired in
both strains of mice. The majority of implantation sites contained
resorbed embryos, and many of the remaining embryos were malformed at
day 14. However, these teratogenic and embryotoxic effects of zinc
deficiency were exacerbated in the MT-I/II KO mice.
|
).
|
). These embryos were 2.6 times as likely to develop abnormally than
were those carried by the control females.
|
Experiment 5 began to address the role of embryonic MT gene expression
to the teratogenic effects of zinc deficiency during pregnancy. There
is normally a Mendelian distribution of the disrupted MT-I/II gene
locus in the progeny of these mice. In this experiment, the
genotypes of the malformed embryos (day 14) were determined by
PCR for the MT-I/II gene disruption (Table 5
). Under these experimental conditions the embryos carried by the
MT-I/II KO mice were 2.19 times as likely to develop abnormally than
were those carried by the control females, which was in agreement with
the above results. Although the sample size in this experiment was
insufficient to detect significant differences, the data suggest that
increased copy number of functional MT-I/II genes in the conceptus
increases resistance to the teratogenic effects of zinc deficiency.
This effect was noted in the MT-I/II KO strain and was more pronounced
in the control strain of mice.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Genetic ablation of the MT-I and
-II genes is phenotypically silent under normal laboratory conditions
in mice. However, the MT are stress proteins, and critical functions of
mammalian MT may, therefore, be revealed only during exposure to
environmental insults. Our studies suggest that one of the
physiological functions of MT is to protect the embryo from the stress
of zinc deficiency during pregnancy. This function provides a
reproductive advantage in mice, when exposed to even moderate dietary
zinc deficiency during pregnancy.
This physiological function of MT was suggested by our previous studies
of transgenic mice that overexpress metallothionein-I. Those mice
accumulate more MT-I and more zinc in major organs than do control
mice (Dalton et al. 1996
), and under conditions of
severe dietary zinc deficiency (1 µg/g dietary zinc beginning on day
1 of pregnancy), the number of resorptions and teratogenic defects of
fetuses were greatly reduced in transgenic compared to control mice.
Recent studies of the MT-I/II KO mice demonstrated impaired intestinal
processing of zinc (Davis et al. 1998
) and impaired
accumulation of zinc in the adult liver (Coyle et al. 1995
, Philcox et al. 1995
), and a recent report
suggests that moderate dietary zinc deficiency during pregnancy in
these mice leads to a more rapid loss of zinc from the placenta and
fetal liver (Rofe et al. 1999
). Our studies reveal that
MT-I and -II can function to protect the developing embryo against
the teratogenic effects of moderate zinc deficiency in utero. After
parturition, maternal dietary zinc deficiency causes abnormal
development of the kidney in neonatal MT-I/II KO mice, but does not
impair kidney function (Kelly et al. 1996
). Thus, all of
the available evidence from genetic studies of the mouse MT-I and
MT-II genes supports the concept that these proteins function in
zinc metabolism. This function becomes critical during pregnancy.
The deficiency of zinc in the diet is a worldwide problem that affects
nearly 1 billion people, and even mild zinc deficiency in pregnant
women diminishes reproductive success (Prasad 1998b
). In
the wild, rodents and other animals must often be exposed to periods of
dietary zinc deficiency. Changes in food source or amount or increased
phytate intake could each affect zinc availability to the
developing embryo. Effects of zinc deficiency during pregnancy occur
rapidly, particularly during the organogenic period, and MT
appears to provide a reservoir of zinc to buffer against this stress.
The mouse embryo is surrounded by cells that constitutively express the
MT-I and MT-II genes (Andrews et al. 1993
),
which may serve to provide a local reservoir of zinc for the developing
conceptus. High-level expression of these MT genes occurs in
maternal, as well as embryonic, tissues in the reproductive tract.
Expression is developmentally regulated in the maternal
deciduum, a tissue which forms from the uterine stroma in
response to embryo implantation (Liang et al. 1996
). The
deciduum surrounds the embryo soon after implantation (day 5)
until about day 12, at which time it has degenerated. High-level
expression of these MT genes also occurs in the visceral yolk sac and
placenta, which are derived from the embryo (Andrews et al. 1993
). Maximal expression of MT genes in the visceral endoderm
and placenta is achieved by days 12–14 of pregnancy. The visceral yolk
sac and placenta develop and differentiate after
decidualization and remain until parturition. Although, these
MT genes are also expressed at low levels in most embryonic cells,
high-level expression occurs in the embryonic liver after day 12
and continues in the fetal and neonatal liver. The maternal pancreas
may also play an important role in zinc homeostasis. Pancreatic MT
concentrations are high relative to that in other maternal organs
during pregnancy, and expression of the pancreatic MT-I and -II
genes and the amount of MT in this organ are dramatically regulated by
dietary zinc. During periods of low dietary zinc, pancreatic MT gene
expression is attenuated, and the protein is degraded and/or released
into the pancreatic juice (De Lisle et al. 1996
). This
loss of MT is remarkably pronounced during the organogenic
period when maternal dietary zinc is limiting (Dalton et al. 1996
).
The critical need to maintain zinc levels has lead to the evolution of
several mechanisms, including the mammalian MT gene system, that
contribute to the homeostasis of zinc during pregnancy. However, MT
genes that are zinc inducible and which encode proteins highly
homologous to mammalian MT are also found in oviparous animals, such as
birds and fishes (Andrews et al. 1996
, Zafarullah et al. 1989
). The zinc needed for development is provided in
the yolk, which acts as a storage depot (Falchuk 1998
).
MT-like proteins are also zinc-inducible in plants and bacteria
(Evans et al. 1990
, Turner et al. 1996
).
Thus, the MT gene system is ancient, which suggests that these proteins
perform a fundamental function(s) in cell physiology. Zinc plays an
essential role in a multitude of cellular processes. Thus, it is
reasonable to assume that the MT first evolved as a mechanism to
control cellular zinc, aiding in protection from deficient and from
excess zinc, and that during evolution this function of MT was adapted
to serve in a wider physiological context.
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FOOTNOTES |
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3 Abbreviations used: KO, knockout; lm, lethal
mouse; MT, metallothionein(s); MTF-1, zinc-finger transcription
factor; MT-I or-II, metallothionein-I or -II; PCR, polymerase
chain reaction; Zn-A, zinc-adequate diet; Zn-D, zinc-deficient;
ZnT, zinc transporter.
Manuscript received March 8, 1999. Initial review completed April 8, 1999. Revision accepted June 1, 1999.
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