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Department of Pathology and Laboratory Medicine, Brown University (J.L., E.B.S., K.B.), Providence, Rhode Island 02912; and the Department of Experimental Radiation Oncology, M. D. Anderson Cancer Center (M.L.M.), Houston, Texas 77030
Address all correspondence and requests for reprints to: Kim Boekelheide, M.D., Ph.D., Department of Pathology and Laboratory Medicine, Brown University, Box G-B518, Providence, Rhode Island 02912. E-mail: kim_boekelheide{at}brown.edu
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Abstract |
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Introduction |
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The occurrence of spontaneous germ cell death in the mammalian testis has been recognized for many years (2, 3, 4). In the case of adult rat testis, a large proportion of type A2, A3, and A4 spermatogonia normally degenerate (5). This form of germ cell death has been studied in detail and is known to be apoptosis (2, 6), a regulated and controlled cell death process with distinct morphological and biochemical characteristics. Enhanced germ cell death occurs after various testicular injuries, including toxicant exposure, alterations of hormonal support, heat exposure, radiation, or treatment with chemotherapeutic compounds (7, 8, 9, 10). In both spontaneous and injury-associated germ cell death, apoptosis appears to be the major pathway of cell death (6, 11).
Recent studies have provided some clues for understanding the underlying molecular mechanisms governing germ cell death in the testis. For example, bcl-2 transgenic mice, in which a human bcl-2 transgene, an antiapoptotic gene, is overexpressed in spermatogonia, have overpopulated spermatogonia and a decreased incidence of germ cell apoptosis (12, 13). Targeted gene disruption of bax, a proapoptotic gene, in mice revealed hyperplasia of spermatogonia as well as massive death of early spermatocytes, suggesting bax-dependent and -independent apoptosis pathways in testis (14). In addition, the tumor suppressor p53, a regulator for both cell proliferation and apoptosis, has been shown to play a role in the testis (15, 16, 17). Mice deficient in p53 exhibit a decreased or delayed onset of germ cell apoptosis induced after radiation exposure or experimental cryptorchidism (16, 17).
The Fas system is a widely recognized apoptosis signal transduction pathway in which a ligand-receptor interaction triggers the cell death pathway (18, 19). Fas (APO-1, CD95) is a transmembrane receptor protein that transmits an apoptotic signal within cells when bound by Fas ligand (FasL, CD95L) (18, 19). The Fas system is involved in maintaining homeostasis in various systems, including maintenance of peripheral T and B cell tolerance, cell-mediated cytotoxicity, and control of immune-privileged sites (19). The Fas system in the testis has been identified as one paracrine signaling system by which Sertoli cells, expressing FasL, can initiate killing of Fas-expressing germ cells (7).
The Fas system model is particularly interesting because it involves an intimate paracrine interaction between Sertoli cells and germ cells during spermatogenesis. For the study of highly interrelated testicular functions, cell type-specific testicular toxicant model systems have been valuable tools, because one can determine the consequences of a perturbation directed to a single cell type. Various testicular toxicants are known that target only germ cells or only Sertoli cells in a very specific manner (20, 21, 22). Radiation exposure primarily targets actively dividing germ cells and acutely increases the incidence of germ cell death, without causing any detectable damage to Sertoli cells (11, 16). One the other hand, both mono-(2-ethylhexyl)phthalate (MEHP) and 2,5-hexanedione (2,5-HD) exposure selectively produce Sertoli cell dysfunction, which subsequently results in massive germ cell loss (23, 24).
In this study, involvement of the Fas system in germ cell apoptosis was tested using various testicular injury models, including germ cell- and Sertoli cell-specific toxicants. We show that the Fas system is activated during germ cell apoptosis after testicular injury and that Fas and FasL are differentially up-regulated depending upon the target cell of the injury.
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Materials and Methods |
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Experimental protocol
Three different treatments were performed to study testicular
germ cell apoptosis in the rat. Radiation exposure was performed as
described by Kangasniemi et al. (25). Adult
LBNF1 rats (10 weeks old) were irradiated with 3.5 Gy and
killed at 0, 3, 6, or 12 h. MEHP (TCI America, Portland, OR)
treatment was performed as described previously (23). Fischer rats (28
days old) received a single dose of MEHP (2 g/kg BW) in corn oil by
gavage. After 0, 3, 6, or 12 h, testes were removed and processed
for frozen sections and isolation of RNA. 2,5-HD treatment was
performed as described by Blanchard et al. (24). Adult
Fischer rats weighing between 150 g and 175 g were treated with
1% 2,5-HD (Aldrich Chemical Co., Inc., Milwaukee, WI) in
the drinking water for 5 weeks. At various times after initiating
exposure (0, 2, 4, 5, 7, and 13 weeks), rats were killed to obtain
testes for frozen sections and isolation of RNA.
Two different treatments were performed to study testicular germ cell apoptosis in the mouse. Radiation exposure was performed as described by Hasegawa et al. (11). Adult C57BL/6 mice were irradiated with 5. 0 Gy and killed at 0, 6, or 12 h. For heat exposure (7), mice (4–6 weeks old) were anesthetized with sodium pentobarbital (40 mg/kg BW; Abbott Laboratories, North Chicago, IL), and their scrotal testes were immersed in a water bath (44 ± 0.5 C) for 15 min. Six or 12 h after immersion, mice were killed, and their testes were removed. For all treatments, at least three animals per time point were used.
Terminal deoxynucleotide transferase-mediated deoxy-UTP nick end
labeling (TUNEL)
For TUNEL staining (26) to detect fragmentation of DNA, the
standard protocol for frozen sections was followed (ApopTag, Oncor,
Gaithersburg, MD). Frozen cross-sections (8 µm) from testes were
prepared, fixed in 10% neutral buffered Formalin for 10 min at room
temperature, rinsed in PBS, postfixed in acetone for 5 min at -20 C,
and then incubated in 2% H2O2 for 15 min to
quench endogenous peroxidases. To quantitate the incidence of apoptosis
at each time point, the number of TUNEL-positive cells within a
seminiferous tubule cross-section was counted. All TUNEL-positive cells
within the seminiferous epithelium were considered as germ cells. The
data were represented as the percentage of seminiferous tubules
containing more than three apoptotic cells of the total number of
seminiferous tubules counted in a cross-section. In control rat testis,
the percentage of tubules with more than three TUNEL-positive cells is
less than 5%, so that an increase in apoptosis is easily determined
using this counting approach. For all experiments, about 300–400
essentially round tubules were counted per time point.
Quantitative RT-PCR
Total RNA was isolated from tissues using Tri-Reagent
(Molecular Research Center, Inc., Cincinnati, OH). First
strand complementary DNA was made using 1–5 µg total RNA in the
presence of Superscript II reverse transcriptase (Life Technologies, Grand Island, NY) and random primer. After the RT
reaction, 1 µl of the incubation mixture was used as a template for
the subsequent PCR reaction. Several primer sets were used to obtain
PCR products of FasL, Fas and ß-actin: rat FasL,
5'-GGAATGGGAAGACACATATGGAACTGC-3' and
5'-CATATCTGGCCAGTAGTGCAGTAATTC-3'; rat and mouse FasL,
5'-ACTC(A/T)CGGAGTTCTGCCAG(C/T)TCCTT-3' and
5'-ATGCAGCAGCCC(A/T/G)T(C/G)AATTACCCAT-3'; rat Fas,
5'-CTGTGGATCATGGCTGTCCTGCCT-3' and
5'-CTCC-AGACTTTGTCCTTCATTTTC-3' mouse Fas,
5'-GAGAATTGCTGAAG- ACATGACAATCC-3'; and
5'-GTAGTTTTCACTCCAGACATTGTCC-3'; rat and mouse ß-actin,
5'-AGGCATCCTGACCCTGAAGTAC-3' and 5'-TCTTCATGAGGTAGTCTGTCAG-3'.
All PCR products were verified by restriction enzyme analysis. For semiquantitative analysis, ß-actin, as an internal control, was coamplified with FasL or Fas messenger RNA (mRNA) by using ß-actin primers (0.1–0.2 µM) and FasL/Fas primers (1 µM). PCR products were collected between 25–40 cycles, and the exponential increase in PCR products was confirmed. All PCR reactions were performed for 35 cycles with an annealing temperature of 55–65 C in 1.5 mM MgCl2.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). A marked increase in the
incidence of TUNEL-positive cells was observed in sections from testes
12 h after radiation (Figs. 1B and 2A). The expression levels of
FasL and Fas mRNA during this time course were determined by
semiquantitative RT-PCR. Fas mRNA up-regulation was prominent 6 and
12 h after radiation; however, FasL expression was not changed
throughout this time course (Fig. 2B).
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Semiquantitative RT-PCR was performed to evaluate the expression level
of FasL and Fas mRNA resulting from 0, 3, 6, and 12 h of MEHP
exposure (Fig. 3B). Up-regulation of Fas was evident at 6 h, with
a further increase evident at 12 h, reflecting the incidence of
germ cell apoptosis (Figs. 3, A and B). However, FasL expression peaked
at 6 h and declined at 12 h, yet remained significantly
higher than the control value (Fig. 3B).
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) (24). FasL expression was clearly induced
after 4 weeks of exposure, and increased Fas expression was evident by
5 weeks (Fig. 3B). The expression level of both genes remained high at
later time points.
Differential up-regulation kinetics of the Fas system in various
testicular injury models
The up-regulation of Fas after injury in all three rat exposure
models and the absence of FasL up-regulation in the radiation model
prompted us to examine additional testicular injury models, including
the evaluation of different species. Semiquantitative RT-PCR analysis
was performed in all model systems to evaluate changes in the
expression level of FasL or Fas mRNA after testicular injuries. The
time-dependent increase in germ cell apoptosis after radiation exposure
or heat exposure in the mouse has been characterized previously in our
laboratories (7, 11). Testes obtained from these experiments were used
to isolate RNA. In agreement with the rat data, up-regulation of Fas,
but not FasL, mRNA was observed in mice exposed to radiation (Fig. 4A). A similar response was observed
after heat exposure in the mouse (Fig. 4B). The expression level of Fas
and FasL mRNA was also evaluated in the Hsp 70–2 knockout
mouse, in which massive death of spermatocytes occurs due to the
failure of meiosis (27). Unlike the wild-type level of Fas expression
in liver, where no abnormalities were observed, testicular expression
of Fas in the Hsp 70–2 knockout mouse was elevated compared
with that in the wild-type and heterozygote. Interestingly, FasL
expression in the mutant mouse was similar to that in the wild-type
mouse.
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Discussion |
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Radiation exposure, a well characterized germ cell injury model, primarily causes DNA damage, leading to either growth arrest or apoptosis (11). In the testis, it has been reported that germ cells, in particular actively dividing spermatogonia, are the main target cells (11, 28, 29). Direct damage to Sertoli cells caused by radiation exposure has not been reported (11, 25). After testicular exposure to 3.5 Gy, up-regulation of Fas was seen as early as 6 h, corresponding with an increasing incidence of apoptosis. In contrast, FasL expression was not changed after radiation exposure, a model in which no Sertoli cell injury is expected.
MEHP and 2,5-HD are two of the best characterized Sertoli cell toxicants (20, 22, 23, 24). After MEHP exposure, Sertoli cell vacuolization and disorganization of vimentin filaments occurs as early as 3 h after exposure, followed by massive germ cell loss by 12 h (23). However, Sertoli cell vacuolization, decreased seminiferous tubule fluid formation, and disorganization of microtubules occur after 3 weeks of 2,5-HD exposure followed by massive germ cell apoptosis at 5 weeks (30, 31, 32, 33). As the modes of action and times of onset of Sertoli cell injury after MEHP and 2,5-HD exposure differ, the up-regulation of both FasL and Fas in these models is best interpreted as a consequence of Sertoli cell injury rather than as a compound-specific effect. This differential expression pattern of FasL was further confirmed by examining two additional model systems, radiation and heat exposure in the mouse.
Up-regulation of Fas, well correlated with the increased incidence of germ cell apoptosis in all model systems tested, suggests that Fas activation is a universal check point for germ cell viability in the testis. Apparently, the multiple sources of cellular injury in the testis lead to increased Fas expression and, thus, increased Fas may serve as a marker for the injured cells (34). This mechanism would ensure rapid elimination of the injured cells, which may be beneficial for the remaining germ cells.
It is intriguing that up-regulation of FasL after MEHP and 2,5-HD exposure preceded the massive germ cell apoptosis. The highest FasL expression was detected 6 h after MEHP exposure, when the incidence of germ cell apoptosis was not yet maximal. Similarly, FasL expression was increased 4 weeks after 2,5-HD exposure, which preceded massive germ cell death at 5 weeks. An early onset of FasL up-regulation after exposure to Sertoli cell toxicants raises the interesting possibility that transcriptional activation of the FasL gene is a molecular sensor that monitors the normal function of the Sertoli cells. Further investigation is required to understand the transcriptional regulation of the FasL gene in the setting of Sertoli cell dysfunction.
Previously, we have proposed the Fas system as a key regulator of the
activation of germ cell apoptosis in normal and injury-associated
conditions (7). The evidence for this model of paracrine death
signaling includes 1) cell type-specific expression of FasL and Fas in
testis, 2) increased survival of germ cells after antisense
oligonucleotide disruption of FasL expression in Sertoli-germ cell
cocultures, and 3) triggering of germ cell apoptosis by an anti-Fas
antibody, which is known to initiate the death cascade (7). The present
study expands on these initial findings by examining both germ cell-
and Sertoli cell-specific testicular injuries. Our results are
summarized as follows: 1) Fas expression is up-regulated after any
treatment which induces massive germ cell apoptosis; and 2) the Fas
system is differentially regulated in the testis depending on the cell
population targeted for injury. Taken together, these data have led to
the development of a working model in which the Fas system actively
controls the equilibrium between the supporting capacity of Sertoli
cells and the number of germ cells in the testis (Fig. 5). We hypothesize that in the normal
state, Sertoli cells express a basal level of FasL, which triggers
apoptosis of a few Fas-positive germ cells. If germ cells, but not
Sertoli cells, are injured, only affected germ cells are eliminated by
the up-regulated expression of Fas. In contrast, after Sertoli cell
injury, the supporting capacity of Sertoli cells is reduced and, as a
result, germ cells cannot be supported adequately. Therefore, the
dysfunctional Sertoli cells increase FasL expression to facilitate the
elimination of the inadequately supported germ cells that express Fas.
As a result, a new equilibrium state is achieved that matches the
reduced supportive capacity of the dysfunctional Sertoli cells with
fewer germ cells.
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Our working model suggests that the differential up-regulation kinetics of the Fas system can be useful in predicting the cell type-specific toxicity of toxicants. Up-regulation of the FasL gene after testicular exposure may be a useful and novel marker to identify a Sertoli cell toxicant. If a toxicant induces up-regulation of FasL, followed by massive germ cell loss, it is likely that the toxicant alters the function of the Sertoli cell. The identification of the target cell of a toxicant is an important step in understanding the underlying mechanisms of toxicant action (20). Only a few testicular toxicants are clearly assigned to a target cell; the cellular targets of many toxicants must still be clarified (21, 22). For example, testicular hyperthermia causes no obvious alterations of Sertoli cells before massive germ cell loss, yet not enough data have been accumulated to exclude the possibility of Sertoli cell injury (21). In this respect, the absence of FasL induction after heat exposure reported here provides additional evidence of germ cell-directed toxicity of heat exposure.
In summary, the present study demonstrates a pathway responsible for germ cell death and complex paracrine control between Sertoli cells and germ cells, which is mediated by the FasL-Fas interaction. Testicular germ cell apoptosis is a fundamental and complex process required for testicular homeostasis during spermatogenesis. Further efforts are required for a more complete understanding of the underlying molecular mechanisms governing this process.
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Acknowledgments |
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Footnotes |
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2 Current address: Division of Pharmacology and Toxicology, University
of Texas, Austin, Texas 78712-1074.
3 Burroughs Wellcome Fund Scholar in Toxicology.
Received July 28, 1998.
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M. J. Scobey, S. Bertera, J. P. Somers, S. C. Watkins, A. J. Zeleznik, and W. H. Walker Delivery of a Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein (CREB) Mutant to Seminiferous Tubules Results in Impaired Spermatogenesis Endocrinology, February 1, 2001; 142(2): 948 - 954. [Abstract] [Full Text] [PDF]
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K. A. Young, G. F. Ball, and R. J. Nelson Photoperiod-Induced Testicular Apoptosis in European Starlings (Sturnus vulgaris) Biol Reprod, February 1, 2001; 64(2): 706 - 713. [Abstract] [Full Text]
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D. M. Creasy Pathogenesis of Male Reproductive Toxicity Toxicol Pathol, January 1, 2001; 29(1): 64 - 76. [Abstract] [PDF]
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 K. Boekelheide, S. L. Fleming, K. J. Johnson, S. R. Patel, and H. A. Schoenfeld Role of Sertoli Cells in Injury-Associated Testicular Germ Cell Apoptosis Experimental Biology and Medicine, November 1, 2000; 225(2): 105 - 115. [Abstract] [Full Text]
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H. Yazawa, I. Sasagawa, and T. Nakada Apoptosis of testicular germ cells induced by exogenous glucocorticoid in rats Hum. Reprod., September 1, 2000; 15(9): 1917 - 1920. [Abstract] [Full Text] [PDF]
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 S. Francavilla, P. D’Abrizio, N. Rucci, G. Silvano, G. Properzi, E. Straface, G. Cordeschi, S. Necozione, L. Gnessi, M. Arizzi, et al. Fas and Fas Ligand Expression in Fetal and Adult Human Testis with Normal or Deranged Spermatogenesis J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2692 - 2700. [Abstract] [Full Text]
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Y. Lue, A. P. Sinha Hikim, C. Wang, M. Im, A. Leung, and R. S. Swerdloff Testicular Heat Exposure Enhances the Suppression of Spermatogenesis by Testosterone in Rats: The "Two-Hit" Approach to Male Contraceptive Development Endocrinology, April 1, 2000; 141(4): 1414 - 1424. [Abstract] [Full Text] [PDF]
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L. Gandini, F. Lombardo, D. Paoli, L. Caponecchia, G. Familiari, C. Verlengia, F. Dondero, and A. Lenzi Study of apoptotic DNA fragmentation in human spermatozoa Hum. Reprod., April 1, 2000; 15(4): 830 - 839. [Abstract] [Full Text] [PDF]
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J. H. Richburg, A. Nanez, L. R. Williams, M. E. Embree, and K. Boekelheide Sensitivity of Testicular Germ Cells to Toxicant-Induced Apoptosis in gld Mice That Express a Nonfunctional Form of Fas Ligand Endocrinology, February 1, 2000; 141(2): 787 - 793. [Abstract] [Full Text] [PDF]
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