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Departments of Anatomy and Cell Biology, McGill University (S.C., L.H.); Department of Pediatrics, Research Center, Sainte-Justine Hospital (S.P.W., L.P., G.M.); Departments of Pediatrics, Human Genetics, and Pharmacology and Therapeutics, McGill University, and McGill University-Montréal Children’s Hospital Research Institute (J.T.), Montréal, Québec, Canada H3H 1P3
Address all correspondence and requests for reprints to: Jacquetta M. Trasler, M.D., Ph.D., McGill University-Montréal Children’s Hospital Research Institute, 2300 Tupper Street, Montréal, Québec, Canada H3H 1P3. E-mail: jacquetta.trasler{at}staff.mcgill.ca
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Introduction |
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HSL is expressed in several nonadipose tissues (12), including the ovary, adrenal gland, heart, skeletal and smooth muscle, placenta, and pancreatic ß-cells, as well as the testis (3, 5, 7, 8, 9, 13, 14, 15, 16, 17, 18, 19). A catalytically active, 120-kDa, testis-specific HSL isoform has been described, which, like the adipocyte isoform, is derived from the LIPE gene (19, 20). The testis-specific isoform is encoded by nine exons (exons 2–10) of the LIPE gene that encodes the adipose HSL isoform, in addition to a 1.2-kb testis-specific exon, located in humans 16 kb upstream of the transcription initiation codon of the adipose isoform, that provides an approximately 36-kDa N-terminal extension (19, 20). In the rat testis, HSL is expressed in the seminiferous tubules in cells close to the lumen and is stage specific, suggesting localization of HSL in late spermatids; HSL expression was undetectable in Leydig and myoid cells (19, 21).
The aim of the present study was to gain a better understanding of the role of HSL in reproduction by examining the fertility and the testes and epididymides of HSL-deficient male mice. For many years HSL has been thought to serve as the principal and possibly unique determinant of lipolysis in adipose tissue, which is believed to be its main biological role. However, HSL-deficient mice have a modest adipose phenotype, with unexpectedly reduced fat mass and unique histological changes and show the presence of a previously unsuspected, HSL-independent, basal lipolytic pathway(s) (22, 23). Our HSL-deficient mouse strain and that reported by Osuga et al. (23) lack both somatic and testis-specific isoforms of HSL. Preliminary results suggested an important effect of HSL deficiency on male fertility. The HSL-deficient mice provide a model to further investigate the role of HSL in male reproductive function. Our results indicate that HSL deficiency results in major defects in spermiogenesis that are incompatible with male fertility and may identify HSL as an interesting target for future male contraceptive development.
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Materials and Methods |
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Fertility assessment
Two-month-old males of the three different HSL genotypes (n
= 5–11 males/genotype) were mated with pairs of 2-month-old CD-1
females (Charles River Laboratories, Inc., St. Constant,
Québec, Canada). Males and females were housed together for 4–5
d, then males were set up again with another two females for an
additional 4–5 d. Females were scored for the presence of copulation
plugs, pregnancy, litter size, and genotype of the offspring. Females
failing to become pregnant after mating with HSL+/-or HSL-/- males were later demonstrated
to be fertile by mating with HSL+/+
males.
Light (LM) and electron (EM) microscopic procedures
For LM and EM, three 6-month-old mice of each genotype were
anesthetized with sodium pentobarbital (Somnitol, MTC Pharmaceuticals,
Hamilton, Canada). Mice were perfusion-fixed through the heart with
5.0% glutaraldehyde in 0.1 M sodium cacodylate buffer (pH
7.4). After the perfusion, the testes and epididymides were removed,
cut into 1-mm3 pieces, processed, embedded in
Epon, and prepared for LM and EM as described previously
(24).
Statistical analysis
Effects of HSL deficiency on organ weights and litter size were
analyzed by one-way ANOVA, followed by Duncan’s multiple range test
(25). The level of significance was taken as
P 
0.05 throughout.
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Results |
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). Virility,
another indicator of androgen status, was similar in the
HSL-/- and the wild-type
mice as judged by the recovery of copulation plugs in the mated
females. In contrast, HSL-deficient mice were completely infertile.
HSL-deficient female mice produced normal sized litters (data not
shown). A clue to the male infertility in the
HSL-/- mice was
testicular weight, which was approximately 50% that in
heterozygous and wild-type animals (Table 1).
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, b and d) compared with
HSL+/+ mice (Fig. 1, a and c). The
reduction in the number of late spermatids (steps 13–16) was evident
in stages I–VIII of the cycle. Other cell types, such as
spermatogonia, spermatocytes, round spermatids (steps 1–7), and
elongating spermatids (steps 8–12), appeared to be comparable in
number to those in wild-type animals.
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, a and c). In
HSL-/- mice, late
spermatids still formed clusters, but the orientation of their heads
appeared random (Fig. 1b). At stage VII of the cycle, the heads of late
spermatids were often clustered and showed abnormal appearances (Fig. 1d). The earliest generation of germ cells to display abnormalities was
step 1 spermatids, which were at times multinucleated (Fig. 2, a and b). Evidence of multinucleation
was also noted in other stages, such that the nuclei often shared a
common acrosome (Fig. 2d). In addition, large cytoplasmic bodies were
evident at varying levels within the seminiferous epithelium (Fig. 2, a
and b, c). These bodies took on a variety of appearances and sizes.
Some were more densely stained (Fig. 2b), whereas others appeared
vacuolated (Fig. 2a). Occasional very large vacuolated bodies resided
in the epithelium (Fig. 2c). Large cavities, which did not appear to
contain any material, were also located within the seminiferous
epithelium (Fig. 2a).
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, step 9–10 elongating spermatids were
simultaneously found with step 1 round spermatids and step 13 late
spermatids. Figure 2c shows early round spermatids associated with step
9 elongating spermatids. It was also noted that some Sertoli nuclei had
relocated from their normal basal position within the seminiferous
epithelium to a higher level within the epithelium (Fig. 2d). At higher
magnification at stage VII, distinct clusters were noted near the
lumen, containing the nuclei of late step 16 spermatids showing
irregular orientations (Fig. 2e).
EM analysis confirmed the observations noted at the LM level.
Multinucleation was evident with numerous nuclei sharing a common
cytoplasm and a common acrosome, as shown in early (Fig. 3a) and midstage round spermatids (steps
7 and 8; Fig. 3b). Multinucleated late spermatids at stage V were also
present within the seminiferous epithelium (Fig. 4a). The late spermatid nuclei had
abnormal shapes, and a common acrosome was often shared by these
nuclei. In some late spermatids, the acrosome maintained close contact
with the grossly malformed spermatid nuclei in part, but also peeled
away (Fig. 4b). This is unlike wild-type late spermatids, whose heads
maintain a distinct sickle or elongated shape and a tapered acrosome
that maintains close association with the nucleus (not shown).
Multinucleated late spermatids sharing the same cytoplasm were also
noted at stage VII (Fig. 4c). The disrupted syncytium contained
numerous late spermatids that appeared to undergo degeneration, as
indicated by the presence of free floating nuclei, membranous profiles,
and incompletely condensed nuclei. The acrosomes lost much if not all
of their contact with the corresponding nuclei; however, most of these
acrosomes still maintained extensive contact with the Sertoli cell
plasma membranes, via their ectoplasmic specializations. Unidentified
granular material was also noted within the cytoplasm of this disrupted
syncytium of cells.
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, b and d, f) compared with wild-type
mice (Fig. 5, a and c, e). However, in contrast, the lumen was filled
with many spherical cells of varying sizes and appearances (Fig. 5, b
and d, f), rather than spermatozoa, as found in wild-type animals (Fig. 5, a and c, e). Condensed heads of spermatozoa were rarely observed in
the epididymides of the HSL-deficient mice.
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, a
and b). The contents of these degenerating cellular bodies appeared to
spill into the epididymal lumen, as evidenced by mitochondria and
numerous membranous profiles of different shapes and sizes within the
lumen (Fig. 6b).
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Discussion |
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The testes of HSL-/- mice showed marked abnormalities in postmeiotic germ cells during spermiogenesis, coinciding with the known testicular expression pattern of HSL (19). In light of minimal effects in other tissues (22, 23), the dramatic effect of HSL deficiency on male fertility suggests this to be the most critical biological function of HSL. Seminal vesicle weights of the HSL-/- animals were comparable to wild-type values, suggesting that androgen production was unaffected. Mating behavior served as an additional indicator of endocrine status. HSL-deficient mice mated normally, as shown by the production of similar numbers of copulatory plugs per mating as in wild-type animals. It is thus unlikely that the infertility was due to an inability to mate or to reduced virility. In their study Osuga et al. (23) reported similar serum T levels in the HSL-deficient mice as in controls.
Morphological testicular abnormalities
The findings of infertility and a reduction in testis
weights were supported by the observation of a reduction in the number
of late spermatids present in the seminiferous tubules of
HSL-/- animals, whereas the
number of spermatogonia and spermatocytes seemed comparable to those in
wild-type mice. It is likely that there is both sloughing of spermatids
from the epithelium as well as degeneration of spermatids within the
tubules, as evidenced by the presence of some degrading,
abnormal-looking, late spermatid heads within the seminiferous
epithelium as well as numerous spherical cells undergoing degeneration
in the epididymal lumen. However, the absence of numerous degenerating
masses as well as lipid droplet accumulation within the seminiferous
epithelium, as seen after vitamin E deficiency (26),
suggests that the majority of spermatids are released into the lumen
and pass into the epididymis. Thus, although late spermatids are
reduced in number, there is no accompanying increase in degenerating
masses within the seminiferous epithelium or in lipid accumulation,
suggesting that Sertoli cells do not play an active role in
phagocytosing the degenerating cells, a function that they perform
under certain conditions (27).
Closer light microscopic observation revealed multinucleated round and elongating spermatids. These multinucleated cells resembled the symplasts that result from intercellular cytoplasmic bridge disruption by cytochalasin D (28), although not with the same extent of multinucleation. Multinucleated giant spermatids have also been reported under various experimental conditions, including exposure to drugs or chemicals such as cimetidine (29), contraceptive agents (30), and herbicides (31), and in transgenic mice, such as those deficient in aromatase (32) and BAX (33). In the cytochalasin D studies, Russell et al. (28) suggested that the cytoplasm left behind by the nuclei that move on to create multinucleated cells joins with cytoplasm from other cells that have lost nuclei to create large cytoplasmic bodies within the seminiferous epithelium. These cytochalasin D-induced cytoplasmic bodies (28) resemble those found within the seminiferous epithelium of HSL-deficient mice, suggesting a common mechanism by which they were formed. At the EM level, the multinucleated spermatids showed nuclei sharing a common acrosome that contorted to follow the abnormal contours of the spermatid nuclei. This suggests that the Golgi apparatus continues to form the acrosome and that the nuclei of spermatids in a common cytoplasm, via receptors on their surface, bind to the acrosome and thus to each other. The disruption of the intercellular cytoplasmic bridges is extensive, and as many as six spermatid nuclei could be seen within a common cytoplasm surrounded by a distended plasma membrane. It must be noted, however, that intercellular cytoplasmic bridges are disrupted only in spermatids, whereas spermatogonia and spermatocytes are apparently unaffected.
In addition to abnormalities noted within single germ cells, it was found that the organization of some seminiferous tubules as a whole was disrupted, as evidenced by apparent asynchronization of spermatogenesis within the seminiferous epithelium. For instance, elongating spermatids were inappropriately found with round spermatids within some tubules. It has been well documented that specific cellular associations form specific stages of the spermatogenic cycle, and therefore certain cell types should not be found simultaneously within a particular tubule (34). In the present study cellular associations of some tubules were not being maintained, and it is possible that some generations of germ cells are delayed during spermatogenesis due to the abnormalities incurred by the absence of HSL. Therefore, they may get left behind while the other generations of germ cells continue in a synchronous fashion through the cycle.
EM observation also showed a disruption in contacts between the acrosome and spermatid nuclei, with the acrosomes often seen peeling off the nucleus. In some cases granular material was noted within the cytoplasm of these disrupted spermatids, indicating the release of protein constituents of the perinuclear theca. It is possible, therefore, that HSL is involved in maintaining the integrity of the acrosomal membrane and/or nuclear membrane. Although some membrane associations appeared disrupted, ectoplasmic specializations (35) in HSL-/- animals remained intact and normal, as seen even in advanced stages of degeneration, as evidenced by the continued tight association of the acrosome of the spermatids to the plasma membrane of Sertoli cells.
Epididymal abnormalities
Both LM and EM analysis have shown that the epididymal lumen was
essentially devoid of spermatozoa. Instead, the cells noted within the
lumen of the epididymis appeared to originate from cells sloughed from
the seminiferous epithelium. EM analysis confirmed that some of these
cells were round spermatids as well as a few abnormal late spermatids,
again suggesting that the seminiferous epithelium cannot fully retain
its normal function in maintaining germ cells. However, although the
lumenal content of the epididymides of the HSL-deficient mice was
clearly abnormal, the epididymal epithelium appeared to be unaffected.
In other conditions, where the epididymal lumen is full of degenerating
cells or abnormal spermatozoa, such as postvasectomy (36)
or in rats treated with chronic doses of cyclophosphamide
(37), epididymal epithelial defects, including the
presence of swollen clear cells filled with numerous endocytic
vesicles, have been seen.
Functional significance of HSL
The mechanism by which HSL is essential to spermatogenesis is
unexplained and may relate to an excess of its multiple substrates,
including triacylglycerols, diacylglycerols, and fatty acyl esters of
cholesterol, retinoic acid, and steroid hormones, and/or to a
deficiency of their hydrolysis products. Evidence of a role for
retinoic acid in the testis is provided by the observations of
spermatogenic defects in retinoic acid-deficient rats (38)
as well as infertility in gene-targeted mice deficient in RAR
(39). In contrast to the late spermatogenic defects in the
HSL-deficient mice, spermatogenesis is disrupted at the preleptotene
spermatocyte and type A spermatogonia stages in retinoic acid
deficiency. Cholesterol is well known to be important in fertility; for
example, in posttesticular sperm maturation (40, 41) and
in sperm capacitation before fertilization (42).
Furthermore, cholesterol distribution in spermatid membranes is highly
organized (43), consistent with a functional
importance of cholesterol in these cells. Based upon the importance of
cholesterol for modifying membrane fluidity (44), it is
tempting to speculate that the striking morphological findings of
abnormal formation of membranous intercellular bridges in germ cells
may relate to this. Membrane biosynthesis does not appear to be
adversely affected in the absence of HSL, as the acrosome is still
being formed, and the size of late spermatids is not hampered during
tail formation. Instead, the spermatid membranes seem unable to
maintain the rigid conformations necessary for the integrity of the
intercellular cytoplasmic bridges (28, 45, 46). Also of
importance is the fact that the intercellular cytoplasmic bridge
disruption in HSL-deficient mice appeared to be restricted to
spermatids, the cells that are known to express HSL
(19).
Osuga’s group also documented male infertility in HSL-deficient mice (23). Testis weights were decreased to a greater extent in our study, to 50% of control values compared with 67% of control values (23); this is perhaps due to the fact that 24-wk-old mice were used in our study, whereas Osuga et al. (23) studied 9- to 14-wk-old animals. Osuga et al. (23) carried out a preliminary examination of testicular histology without reporting on stage-specific effects or EM findings and noted extensive vacuolization within the seminiferous tubules; they suggested that the vacuoles might contain cholesterol esters. Our study was carried out on perfused tissues to optimize the morphological integrity of the testicular tissue. Vacuoles were occasionally noted, but after careful examination at both the LM and EM levels, there was little evidence of cholesterol ester accumulation within the epithelium. A careful developmental study as well as alternate techniques to detect accumulations of cholesterol esters in the seminiferous epithelium may help to determine the mechanistic basis of the infertility in HSL deficiency as well as to delineate the basis for some of the differences between the two HSL-deficient mouse models.
On a practical level, HSL may be implicated in some cases of male infertility and could represent a potential target for the development of an effective male contraceptive.
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Footnotes |
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1 J.T. and L.H. made equal contributions to these studies, and the
order of their names is arbitrary. 
Abbreviations: EM, Electron microscopy; LM, light microscopy; HSL, hormone-sensitive lipase.
Received March 26, 2001.
Accepted for publication June 7, 2001.
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mutant mice. Proc Natl Acad Sci USA 90:7225–7229This article has been cited by other articles:
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