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-Glutamyl Transpeptidase-Deficient Mice1
Departments of Pathology (T.R.K., A.L.W., G.K., S.V.K., M.M.M., M.W.L.), Molecular and Cellular Biology (T.R.K., M.M.M., M.W.L.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Michael W. Lieberman, M.D., Ph.D., Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mikel{at}bcm.tmc.edu
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Abstract |
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-glutamyl transpeptidase (GGT) are growth retarded
as a result of cysteine deficiency secondary to excessive glutathione
excretion in urine and display coat color defects and cataracts.
Although GGT is widely expressed throughout the mouse reproductive
axis, little is known about its role in reproduction. Here, we present
an analysis of the reproductive phenotypes of GGT-deficient mice.
Mutant male mice have reduced testis and seminal vesicle size and
suppressed serum insulin-like growth factor I and FSH levels and are
infertile. Although these mice are severely oligospermic, histological
analysis of testes reveals grossly normal stages of spermatogenesis,
including late stage spermatids, but the tubule diameter is reduced.
GGT-deficient female mice are also hypogonadal and infertile. At 6
weeks of age, the ovaries of mutant mice are histologically
indistinguishable from those of its wild-type counterpart. However, the
absence of antral follicles and corpora lutea and follicular
degeneration are apparent by 11–13 weeks. In addition, immature female
mutant mice (at 21–23 days) are insensitive to exogenous gonadotropin
administration and fail to superovulate, suggesting an intraovarian
defect. Consistent with these mutant phenotypes, HPLC analysis of adult
mutant testes and ovaries showed a reduction in intracellular cysteine
levels. Administration of N-acetylcysteine in the
drinking water beginning on day 21 to mutant mice for 2 weeks restored
testis, seminal vesicle, and ovary sizes to values comparable to those
in wild-type mice. Furthermore, N-acetylcysteine-fed
(continuously) mutant male and female mice were fertile and produced
normal numbers of offspring when mated to wild-type control mice. These
results demonstrate that GGT itself is not necessary for reproductive
function. However, GGT plays an important role in cysteine homeostasis
within the mouse reproductive axis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-glutamyl
transpeptidase (GGT) and membrane-bound dipeptidases (3, 4) that supply amino acids for GSH synthesis and protein
synthesis. GGT is widely expressed in many mammalian tissues and is
essential for catalyzing secreted GSH into cysteinyl-glycine and
-glutamic acid. After cleavage of cysteinyl-glycine by dipeptidase,
the amino acids are reabsorbed and used to synthesize GSH, a process
termed the -glutamyl cycle (3, 4). The generation of
GSH is crucial for the protection of cells against oxidative stress and
other forms of cellular injury resulting from cytotoxic and
carcinogenic xenobiotic compounds. Thus, GSH serves as a cysteine
reserve and acts as a major antioxidant in many physiological processes
(5, 6). GGT mobilizes cysteine from this pool and makes it
available to many tissues (5, 6). In the male reproductive axis of many species, GGT is widely expressed, including the testis, seminal vesicle, and epididymis (7, 8, 9, 10, 11), with the highest levels of GGT expression found in the epididymis. At least four different isoforms of GGT are expressed in the initial segment of the rat epididymis, but their functional significance remains unknown (12). Depletion of GSH in rat male reproductive tissues by intratesticular injection of various chemicals results in alterations in sperm chromatin structures, leading to defective sperm maturation and abnormal sperm motility (13). Some of the defects in sperm function in human patients with dyspermia resulting from varicocele or genital tract infection can be improved by systemic supplementation of GSH (14). Intracellular GSH levels are also known to be important for direct protection against oxidative injury to the testis, epididymis, and sperm (15, 16). However, it is not known whether any or all of these effects are mediated via GGT.
Relatively less is known about the distribution of GSH and expression of GGT in the ovarian follicle and the follicular microenvironment. Recently, the intraoocyte GSH content has been shown to be important during fertilization for sperm penetration of the egg, decondensation of the sperm nucleus, and subsequent formation of the male pronucleus (17). Although follicular atresia can be induced by oxidative damage to the oocyte, the roles of GSH and/or GGT in this process are not clearly known. Similarly, it is unknown whether intraovarian levels of GGT (and GSH) can influence follicular development, leading to normal ovulation and subsequent fertilization of ovum by sperm.
Although GGT is widely expressed in many reproductive organs, it has not been possible to use in vivo studies to examine its role in maintaining normal male and female reproductive function. We have previously generated GGT-deficient mice by gene targeting in embryonic stem cells (18). These mice have multiple metabolic defects that manifest as severe growth retardation, reduction in intracellular GSH and cysteine pools, coat color defects, and cataracts (13). Here, we report the characterization of the reproductive defects in these GGT-deficient mice.
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Materials and Methods |
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Histological analysis
Ovaries from wild-type (WT) control and GGT-deficient female
mice (at 6, 11, and 13 weeks of age) were fixed in buffered formalin
(pH 7.0) for at least 24 h at room temperature and processed for
paraffin embedding using standard protocols as previously described
(19). Four-micron sections were cut and stained with
periodic acid-Schiff (PAS)/hematoxylin for light microscopy. Testes
were fixed in Bouin’s reagent (Sigma, St. Louis, MO) for
12–14 h for better visualization of the tubule architecture,
extensively washed in LiCO3-saturated 70%
ethanol to remove the excess picric acid, and stored in 70% ethanol at
room temperature. Paraffin-embedded 4-µm sections were later stained
with PAS/hematoxylin as previously described (19).
Immunohistochemistry
Adult male mice (WT and GGT deficient) were transcardially
flushed with 0.9% saline and perfused with 30 ml cold paraformaldehyde
(4% in PBS, pH 7.2), after which the pituitaries were removed and
postfixed overnight in 10% sucrose containing 4% paraformaldehyde (pH
7.2) at 4 C. Frozen sections [14 µm; in OCT medium (Miles
Laboratories, Elkhart, IN)] were then cut and immunochemically stained
with LHß-, FSHß-, and GH-specific polyclonal or monoclonal
antibodies (NIDDK reagents, Medix, Inc., Foster City, CA) and
visualized with appropriate fluorescein isothiocyanate- or rhodamine
isothiocyanate-conjugated secondary antibodies using an epifluorescence
microscope (Carl Zeiss, Inc., New York, NY) as described
previously (19).
RIAs
Adult mice were anesthetized with Metofane (Mallinckrodt, Inc., Mundelein, IL) and exsanguinated by closed cardiac
puncture. Serum samples were collected in Microtainer serum separator
tubes (Becton Dickinson and Co., Franklin Lakes, NJ) and
stored frozen at -20 C for RIA analysis. Serum FSH was measured using
a NIDDK rat FSH RIA kit (sensitivity, 3 ng/ml; intraassay coefficient
of variation, 1.9%; interassay coefficient of variation, 5%), serum
GH was measured by an enzyme-linked immunosorbent assay method using
Amersham Pharmacia Biotech’s rat GH enzyme-linked
immunosorbent assay kit (sensitivity, 1.6 ng/ml; intraassay coefficient
of variation, 3.3%; interassay coefficient of variation, 8.3%). Serum
insulin-like growth factor I (IGF-I) was measured by an acid-ethanol
extraction method using an INCSTAR Corp. (Stillwater, MN)
RIA kit (sensitivity, 3.8 nmol/liter; intraassay coefficient of
variation, 8.4%; interassay coefficient of variation, 12.5%). GH and
IGF-I assays were validated for measuring the mouse hormones. Rat GH
and mouse GH are highly identical. Similarly, human IGF-I antibody does
not distinguish between human and mouse antigens that are 94%
identical. Testosterone levels in serum samples were measured by a
solid phase RIA kit (Diagnostic Systems Laboratories, Inc., Webster, TX) according to the manufacturer’s instructions
(sensitivity, 0.08 ng/ml; intraassay coefficient of variation, 9.6%;
interassay coefficient of variation, 8.6%). Serum estradiol levels
were measured by a liquid phase double antibody RIA kit
(Diagnostic Systems Laboratories, Inc.; sensitivity, 2.2
pg/ml; intraassay coefficient of variation, 6.5%; interassay
coefficient of variation, 7.5%).
Determination of intracellular cysteine and GSH by HPLC
GSH and cysteine in testes, seminal vesicles and ovaries were
determined by a highly sensitive HPLC/electrochemical Coularray
system (ESA, Boston, MA) (20). GSH and cysteine were
separated on a reverse phase 5-µm Inertsil ODS 2 silica column (250
x4.6 mm i.d.) using a mobile phase containing 0.1 mM
monochloroacetic acid, 2.5% methanol, 0.87%
N,N-dimethyl formamide and 3.3
mM heptane sulfonic acid (pH 2.8). The cell
potential of the Coularray system was set at 800 mV. The intracellular
cysteine and GSH levels were expressed as micromoles per g tissue.
N-Acetylcysteine (NAC) feeding regimens
NAC (Sigma, St. Louis, MO) was dissolved in the
drinking water (10 g/liter) and supplied ad libitum. For
rescue experiments, GGT-deficient mice were NAC supplemented beginning
at 2–3 weeks of age and continued beyond 12–14 weeks. For time-course
experiments, mice were fed NAC in drinking water beginning at 3 weeks
of age until 6 weeks of age and were withdrawn periodically at 0
h, 72 h, 7 days, and 10 days. At each point, mice were killed, and
serum and reproductive organs were collected for further analyses.
Evaluation of sperm parameters
Epididymal sperm (from both sides) was extracted into 1 ml M2
medium and analyzed for motility and viability as described previously
(19). Sperm number was manually counted using a
hemocytometer.
Superovulation experiment
Immature female mice (21–23 days) were PMSG primed (5 IU/100
µl, ip), and 48 h later were given hCG (5 IU/100 µl, ip) and
mated to WT or GGT-deficient male mice. The mice were monitored for
vaginal plugs the next morning. Embryos from oviducts were collected
into modified Whitten’s (KSOM) medium (PGC Scientifics,
Gaithersburg, MD) and counted as previously described
(19).
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Results |
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). At 8 weeks or earlier time points,
GGT-deficient male mice had decreased testis size, and the accessory
glands (i.e. epididymis and seminal vesicle) were severely
hypoplastic. Serum testosterone levels were significantly low in mutant
males compared with those in age-matched WT mice [0.7 ± 0.3
ng/ml (n = 6) vs. 13.4 ± 5 ng/ml (n = 5);
P < 0.01]. Although histological analysis of testis
from mutant mice revealed normal development of the spermatogenic and
somatic cells of the testis (Fig. 1E), there was a massive reduction in
epididymal sperm number (Table 1), and
the few sperm present were immotile. There were no additional
testicular phenotypes when male mice were examined up to 13 weeks of
age. The testicular weights were significantly decreased compared with
those in WT littermates [83.7 ± 3.7 mg (n = 7)
vs. 109.2 ± 3.5 mg (n = 5); P <
0.001]. Testicular histology at 13 weeks was no different from that at
6–8 weeks of age (data not shown). Similarly, serum testosterone
levels were also suppressed at this age compared with those in WT
littermates [0.3 ± 0.03 ng/ml (n = 4) vs.
18.4 ± 1.3 ng/ml (n = 3); P < 0.01]. Thus,
these results indicate that the absence of GGT leads to male
infertility, decreased testis size, oligospermia, and hypoplastic
secondary male sex organs in male mice.
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). Histological
analysis of the mutant ovary at 6 weeks demonstrated normal follicles
in stages comparable to those seen in the ovary of a WT control female
mouse (Fig. 2, A and B). Many primordial follicles, one-layer and
multilayered primary follicles, and small preantral stage follicles
were apparent; these were indistinguishable from those in a WT control
female mouse ovary. Whereas many antral follicles and corpora lutea
were readily apparent in 10- to 11-week-old WT mouse ovaries, they were
absent in the mutant ovary (Fig. 2, C–E). In addition, at this and
later stages, the mutant ovary demonstrated many more degenerating
oocytes (Fig. 2F). Histological analysis also indicated that the mutant
female mice were not cycling. Serum estradiol levels were marginally
detectable in WT females (2.1 ± 0.6 pg/ml; assay sensitivity, 2.2
pg/ml) at 42 days, whereas they were undetectable in the age-matched
mutant female mice. Superovulation treatment of immature female mutant
mice (n = 10) and subsequent mating to male mice did not result in
obvious vaginal plugs and increased numbers of fertilized oocytes
in vivo in the oviducts. These results indicate that
GGT-deficient female mice are infertile and insensitive to exogenous
gonadotropin administration. They also demonstrate intraovarian defects
leading to progressive degeneration of oocytes.
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), they were marginally increased in mutant
female mice (data not shown). These data are consistent with decreased
testis size in GGT-deficient male mice and with a possible intraovarian
defect (and a failure to respond to superovulation) in GGT-deficient
female mice. Qualitative immunohistochemical analysis of the mutant
male mouse pituitary revealed normal distribution of GH-, LH-, and
FSH-positive cells (data not shown).
Intracellular cysteine levels are decreased in the reproductive
organs of GGT-deficient mice
GGT plays a major role in maintaining intracellular cysteine and
GSH pools (4). We have previously demonstrated that
cysteine levels are decreased in several tissues, including the liver,
brain, kidney, and lung, of GGT-deficient mice (18). To
assess whether the mutant phenotypes are related to changes in
intracellular thiols in the testes, seminal vesicles, and ovaries of
GGT-deficient mice, we measured cysteine and GSH levels at 6 and 13
weeks of age and compared them to levels in WT controls. Cysteine
levels were significantly (P < 0.001) reduced in the
testes of mutant mice compared with those in age-matched WT controls
(Fig. 3), whereas no changes in cysteine
levels were found in the seminal vesicles of mutant mice. Although
there was no change in cysteine levels in the ovaries of mutant mice at
6 weeks of age, there was a marginal reduction (P =
0.07) at 13 weeks compared with those in WT controls (Fig. 3). In
addition, the ovarian cysteine levels of 13-week-old mutant mice were
significantly (P < 0.01) lower than those in mutant
mice at 6 weeks of age (Fig. 3). Despite these changes in cysteine
levels, GSH levels remained unchanged in the testes and ovaries of
mutant mice (data not shown).
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NAC treatment rescues the reproductive defects in both male and
female GGT-deficient mice
Treatment of GGT-deficient mice with NAC (drinking water),
initiated at 3 weeks of age and continued up to a minimum of 6 weeks or
beyond, restores the growth of these mice (18). They also
display normal coat color and normal eye lens morphology and are
indistinguishable from WT siblings (18) (Chevez-Barrios,
P., and M. W. Lieberman, unpublished data). To determine whether
these mice also become reproductively competent, we analyzed the
reproductive organs of these mice morphologically, histologically, and
functionally. NAC treatment completely restored the fertility in female
GGT-deficient mice. The female reproductive tracts from these mice were
morphologically and histologically indistinguishable from those WT mice
at 6 and 9 weeks (data not shown). In addition, 3 of 3 NAC-rescued
female mice were fertile and upon mating delivered normal numbers of
pups (number of pups, 7.3 ± 0.3; number of litters,
6).
Similarly, NAC treatment rescued the reproductive phenotype in
GGT-deficient male mice. The sizes of the testis and accessory glands
(epididymis and seminal vesicles) were comparable to those in WT
age-matched control mice (Table 3; Fig. 1, A—C; and data not shown). These male mice (19 of 22) were also
fertile at 6 weeks or later when mated to control female mice and sired
normal offspring (number of pups, 8.3 ± 0.2; number of
litters, 104). To further determine the sensitivity of the male
reproductive organs to NAC levels, we supplemented NAC and studied the
effects of withdrawal of NAC in GGT-deficient male mice. As shown in
Tables 3 and 4, NAC withdrawal did not
cause alterations in testis size or epididymal sperm number, motility,
or viability up to 10 days. Whereas NAC withdrawal caused a progressive
moderate decrease in epididymal size, the seminal vesicles were more
severely affected by 72 h. By 10 days of NAC withdrawal, the
seminal vesicles were more severely atrophic, with an approximately
60% reduction in size. Together, these results demonstrate that
continuous NAC treatment restores fertility in GGT-deficient mice.
Furthermore, these results indicate that seminal vesicles and
epididymis, unlike testis, are sensitive to intracellular cysteine
pools.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast to ovarian defects in mutant females, multiple reproductive tissues are affected in GGT-deficient males. The testis, seminal vesicles, and epididymis are decreased in size, and the mutants display severe oligo- or azoospermia. In addition, sperm motility in the mutants is completely abolished. Seminal vesicles are much more affected and are completely hypoplastic, consistent with androgen deficiency in the serum of mutant male mice. Antioxidants also play a major role in sperm capacitation and are important for sperm function and characteristics (29). It remains to be established what stage is critically affected in sperm function in the complete absence of GGT and decreased intracellular cysteine levels (see discussion below). We also do not know whether sperm from GGT-deficient mice are competent to fertilize eggs. In vitro fertilization experiments will allow us to analyze this in the future.
The reproductive defects in male and female GGT-deficient mice could result directly from decreased intracellular cysteine levels in reproductive organs or via secondary events, such as overall metabolic and hormonal imbalances. Interestingly, GSH levels remained unchanged in the testes, ovaries, and seminal vesicles of mutant mice. This is different from several other mutant mouse tissues, including liver, brain, and spleen, in which we previously (18) found a concomitant decrease in plasma cysteine levels and a decrease in intracellular GSH levels. The high levels of GSH in ovary and testis (compared with other organs in GGT-deficient mice) may result from a direct uptake of GSH intracellularly. Although such uptake is not generally believed to occur in most organs (4), there are data demonstrating this uptake in the reproductive axis (29).
GGT-deficient mice can be completely rescued by NAC administration. This restoration also includes male and female fertility. Both male and female mice treated with NAC had normal litter sizes and offspring. Although we have not measured cysteine levels in the reproductive organs of NAC-treated mutant mice, our previous studies (18) suggest that NAC supplementation restores intracellular cysteine levels to normal. In addition, the NAC withdrawal experiments with male mice suggest that intracellular cysteine levels are essential for normal seminal vesicle and epididymal growth. In addition to affecting normal metabolism, GGT/cysteine may be important for the expression of some critical genes that affect seminal vesicle growth and differentiation.
GGT-deficient mice have altered hormone profiles in serum. In particular, serum IGF-I levels are completely suppressed, whereas serum GH levels are slightly elevated, consistent with a dwarf phenotype of these mice. Infertility is often observed in mice with a dwarf phenotype (30, 31). These phenotypes are also consistent with those seen in GH receptor knockout mice (32), but are more severe in GGT-deficient mice. Although the majority of GH receptor knockout female and male mice are fertile, they have elevated serum GH levels and reduced IGF-I levels and display multiple reproductive defects (32). Additionally, IGF-I-deficient female mice are infertile, and their ovaries demonstrate a preantral stage block of folliculogenesis due to reduced expression of FSH receptor on granulosa cells (33). IGF-I-deficient female mice also do not respond to gonadotropins for ovulation induction (33). Serum FSH levels are suppressed in male, but not female GGT-deficient, mutant mice. This sexually dimorphic expression of FSH is well known and is normally attributed to differences in the actions of the gonadal peptides, inhibin and activin, and the gonadal steroids between the two sexes (34, 35).
Based on our data, we hypothesize that the male and female reproductive phenotypes in GGT-deficient mice are the result of a combination of a reduction in intracellular cysteine levels and trophic factors. As intracellular cysteine levels in seminal vesicles of mutant mice are not altered, the hypoplastic phenotype may be attributed to a trophic effect. In contrast, our data suggest that the testicular phenotype may result from altered trophic factor signaling and a reduction in intratesticular cysteine levels. The reduced testosterone levels in the serum (of mutant male mice) reflect the hypoplastic accessory glands and reduced spermatogenesis, whereas the ovarian phenotype may result predominantly from a decrease in intracellular cysteine levels and other intraovarian defects. Additionally, infertility in the mutant mice could be due to behavioral defects, such as altered copulatory behavior, inability to mount, etc. Although human siblings with GGT deficiency have been reported (3, 4), we cannot compare the reproductive phenotypes in GGT-deficient mice, because in humans there are multiple GGT genes, whereas in the mouse GGT is a single copy gene (3, 4). In addition, no reproductive defects were reported in humans with GGT deficiency.
In summary, we have analyzed the reproductive defects in GGT-deficient mice. Our results provide direct in vivo evidence that GGT itself is not required for normal reproductive function. However, adequate levels of intracellular GSH and cysteine, which are regulated by GGT, are essential for normal reproductive function. These mutant mice offer a useful model to further understanding of the consequences of altered cysteine levels in follicular maturation and sperm function leading to male and female infertility in humans.
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Acknowledgments |
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Footnotes |
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Received January 19, 2000.
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References |
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