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Sphingolipid signaling in gonadal development and function
Chemistry and Physics of Lipids 102 (1999) 149 – 155 www.elsevier.com/locate/chemphyslip
Sphingolipid signaling in gonadal development and function Jonathan L. Tilly a,*, Richard N. Kolesnick b a
Vincent Center for Reproducti6e Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Har6ard Medical School, VBK137E-GYN, 55 Fruit Street, Boston, MA 02114, USA b Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Abstract Sphingolipid second messengers, such as ceramide and sphingosine-1-phosphate, signal proliferation, differentiation and death in mammalian cells. The object of this article is to highlight the potential impact of this new information on the study of female and male gonadal development and function. Since the generation of competent gametes by both sexes is precisely regulated by maturational (meiotic) and apoptotic (quality-control) checkpoints, it is proposed that lipid signaling molecules serve as important contributors to the regulation of gametogenesis. The function of sphingolipid molecules in mediating stress- or damage-induced apoptosis in the germ line, an event most-likely associated with impaired gonadal function and infertility, is also discussed. Collectively, these areas represent exciting research directions that may ultimately lead to the development of new therapeutics to coordinate and control fertility in males and females. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Ceramide; Sphingomyelinase; Apoptosis; Germ cell; Oocyte; Sperm; Ovary; Testis
1. Introduction It has been long-recognized that many cell types present in tissues associated with reproduction generate sphingolipid molecules, and in particular ceramide, as mediators or modifiers of hormone action. Only recently, however, has increasing attention been focussed on the function of lipidderived second messengers in modulating apoptosis in reproductive tissues, a research area that has gained considerable notoriety in recent work using a variety of cell lines as well as several * Corresponding author. Tel.: +1-617-7242182; fax: +1617-7267548. E-mail address: [email protected] (J.L. Tilly)
tissues outside of the female and male reproductive systems (reviewed in Spiegel et al., 1996; Haimovitz-Friedman et al., 1997a,b; Spiegel et al., 1998). The purpose of this article is to briefly review the current literature regarding sphingolipid signaling events involved in transducing information provided by external stimuli in cellular development and death in the male and female gonads. This area of investigation represents a new research avenue of considerable significance for both basic biology and clinical medicine since apoptosis in the ovary (reviewed in Tilly et al., 1997a; Tilly, 1998) and testis (reviewed in Dunkel et al., 1997a,b) is central to normal gametogenesis as well as to pathologic gonadal failure. Where appropriate, testable hypotheses will therefore be
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offered as a means to encourage further research into the possible roles of abnormal sphingolipid signaling in the etiology of infertility.
2. Sphingomyelinases and ceramide in gamete maturation Accessory glands of the male reproductive system, such as the seminal vesicles, appear to be major contributors of a number of hydrolytic enzymes, including a cation (cobalt, manganese)sensitive sphingomyelinase, to seminal fluid (reviewed in Vanha-Perttula et al., 1990). The function of these enzymes in semen remains to be fully elucidated, although it has been speculated that hydrolysis of phospholipids on the outer surface of ejaculated male gametes, or perhaps even those present in seminal fluid, may be involved in various sperm functions including capacitation, the acrosome reaction and sperm – egg binding (Vanha-Perttula et al., 1990; Hall et al., 1991). Interestingly, spermatozoa possess high levels of inherent neutral sphingomyelinase activity (Hinkovska et al., 1987), consistent with an earlier study that identified both neutral and acid sphingomyelinase activities in the testis (Spence et al., 1979). It has been recently shown that human sperm maturation during epididymal transport is associated with dramatic changes in the lipid composition of spermatozoal plasma membranes, most notably an increase in phosphatidylcholine with corresponding decreases in phosphatidylserine, phosphatidyl ethanolamine and sphingomyelin (Haidl and Opper, 1997). These findings, taken with the observation that immature and immotile sperm harvested from the caput epididymides gain progressive motility upon phosphatidylcholine exposure in vitro (Haidl et al., 1993), support the hypothesis that a change in sperm plasma membrane lipids, likely mediated at least in part by seminal fluid-derived or intrinsic sphingomyelinase(s), is an important component of male gamete maturation. Additional studies are required, however, to confirm that alterations in spermatozoal plasma membrane content of phosphatidylcholine and/other lipid molecules are in
fact critical for development of sperm motility. In addition, future experiments are needed to assess the functional role of other bioactive sphingolipid molecules known to be present at high levels in the testis, such as sphingosine-1-phosphate (Yatomi et al., 1997), in male gametogenesis and sperm maturation. By comparison, very little is known of the possible function of sphingolipid molecules in female gamete development. The majority, if not all, data available regarding the effects of ceramide and other lipid second messengers in regulating oocyte maturation have been derived from studies of progesterone-induced meiotic cell cycle progression in Xenopus lae6is. For example, induction of H1 kinase activity and germinal vesicle breakdown, two markers of oocyte maturation, can be induced by brief exposure of Xenopus oocytes to bacterial sphingomyelinase (derived from Staphylococcus aureus) in vitro (Strum et al., 1995; Morrill and Kostellow, 1998). These effects can be mimicked by exogenous ceramide or sphingosine, delivered either by inclusion in the culture medium or by microinjection (Strum et al., 1995; Morrill and Kostellow, 1998). Further evidence that these sphingolipid messengers mediate the actions of progesterone, the physiological agent responsible for Xenopus oocyte maturation, is provided by findings of a rapid generation of ceramide in oocytes following progesterone treatment with a concomitant decrease in sphingomyelin content due to activation of a magnesium-dependent neutral sphingomyelinase (Strum et al., 1995; Morrill and Kostellow, 1998). Whether or not a similar role exists for sphingomyelinase-catalyzed ceramide generation in the resumption of meiosis in mammalian oocytes remains to be established.
3. Sphingomyelinases and ceramide in gonadal cell apoptosis Since we are unaware of any published evidence of a direct role for ceramide or sphingosine derivatives in mediating male germ cell death during spermatogenesis or following a pathologic stress to the testis, the majority of this section will
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be devoted to a discussion of the female gonad. However, two studies have provided information that may prove useful for interpreting future experiments on the role of sphingolipid molecules in regulating cell death in the testis (for review of the regulation and significance of apoptosis in the testis, see Dunkel et al., 1997a,b). First, sphingomyelinase has been reported to inhibit basal and gonadotropin-stimulated testosterone production, as well as to decrease gonadotropin binding to its receptor and gonadotropin-promoted cAMP production, in cultured rat Leydig cells (Degnan et al., 1996) Considering the importance, if not the requirement, of androgen biosynthesis by Leydig cells in maintaining spermatogenesis and germ cell survival in the mammalian testis (Tapanainen et al., 1993; Dunkel et al., 1997c; reviewed in Dunkel et al., 1997a,b), these findings suggest that sphingomyelinase-mediated reductions in steroid output within the testis could indirectly lead to excessive spermatogonial and spermatocyte apoptosis. The second report pertaining to the testis is somewhat more indirectly associated with a role for ceramide in male germ cell death, that being the proposed involvement of the Fas – Fas ligand system in deleting germ cells during spermatogenesis in the rat testis (Lee et al., 1997). Since Fas ligation in some (De Maria et al., 1998), but not all (Watts et al., 1997; Hsu et al., 1998), cell types is known to cause an elevation in intracellular ceramide levels as a potential mediator of apoptosis induced by this cytokine, it is possible that activation of Fas-mediated death in male germ cells is transduced via the ceramide pathway. Moreover, data provided by Lee et al. (1997) also showed that significant numbers of male germ cells become Fas-positive, and in turn more sensitive to Fas ligand-induced apoptosis, in response to treatment of rats with biohazardous chemicals. Assuming the involvement of ceramide in this paradigm of testicular cell death as well, these findings, which implicate the Fas pathway as a ‘sensor’ of toxicant-induced testicular damage, would be in agreement with previous data linking ceramide to apoptosis induced by a variety of physiologic and pathologic stressors (Verheij et al., 1996). These hypotheses regarding the poten-
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tial involvement of ceramide in Fas-mediated male germ cell death, however, await testing in future investigations. The direct involvement of sphingomyelinasegenerated second messengers in mediating cellular function, and more recently cellular life and death decisions, in the female gonad is somewhat more defined (for review of apoptosis in the ovary, see Marita and Tilly, 1999; Tilly and Robles, 1999). One of the earliest reports of a function for sphingolipid molecules in the ovary proposed a role for ceramide as being responsible for the inhibitory actions of tumor necrosis factor alpha (TNFa) on gonadotropin-promoted aromatase activity, and hence estradiol biosynthesis, in cultured rat granulosa cells (Santana et al., 1995). In addition to showing that both bacterial sphingomyelinase and a short-chain membrane-permeable analog of ceramide (N-acetylsphingosine) could mimic the effects of TNFa, these authors also demonstrated a rapid decrease in sphingomyelin with a corresponding elevation in endogenous ceramide in TNFa-treated granulosa cells. This study was shortly followed by a comparable series of investigations on the role of sphingomyelin hydrolysis and the ensuing generation of ceramide as effectors of interleukin-1 beta (IL1b)-regulated steroid and prostaglandin production in cultured granulosa cells (Santana et al., 1996a). Although these two papers clearly demonstrated that ovarian follicular granulosa cells possess a hormonally-modulated sphingomyelinase activity and are capable of generating ceramide as a second messenger, it remained to be established whether or not these early signaling events also participated in determining granulosa cell fate. A comprehensive series of experiments by Witty et al. (1996) then clearly established a connection between ceramide and apoptosis induced in avian ovarian granulosa cells by either serum-starvation or exposure to acute pathologic stress. In the case of tropic hormone deprivation-induced apoptosis, a membrane-permeable ceramide analog was found to further exacerbate basal levels of granulosa cell death as well as completely override the survival actions of a cAMP analog. Moreover, apoptosis initiated in granulosa cells as a result of exposure to a common anti-cancer drug (i.e.
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daunorubicin), but not to ultraviolet (UV) irradiation, could be completely suppressed by pretreating the cells with the ceramide synthase inhibitor, fumonisin-B1 (Witty et al., 1996). These latter observations fully support a previous report using fumonisin-B1 in a human leukemia cell line that first proposed a role for de novo ceramide synthesis as a novel effector of apoptosis in cancer cells treated with chemotherapeutic drugs (Bose et al., 1995). Additionally, the inability of fumonisin-B1 to protect granulosa cells from apoptosis caused by UV irradiation is similar to published data identifying a requirement for acid sphingomyelinase (as opposed to ceramide synthase) in ceramide generation required for radiation-induced apoptosis in lung endothelial cells (Santana et al., 1996b) and in UV-induced activation of c-Jun N-terminal kinase (JNK) (Huang et al., 1997). This work with avian granulosa cells (Witty et al., 1996) was paralleled by studies with rat ovarian follicles maintained in vitro, in which membrane-permeable ceramide analogs were shown to both accelerate basal apoptosis in cultured follicles (Tilly et al., 1996) and to completely antagonize gonadotropin-promoted follicular cell survival (Kaipia et al., 1996). Studies of the rat ovary have further indicated that the second functionally-important somatic cell lineage of the ovarian follicle, theca-interstitial cells, also appear to possess a cytokine-activated signal transduction pathway coupled to ceramide-induced apoptosis (Foghi et al., 1998). Additionally, endogenous ceramide levels are elevated in cultured rat ovarian follicles at a time associated with the onset of apoptosis in this model (Tilly et al., 1997b), and exogenous ceramide analogs have been reported to rapidly induce activation of the stress-related kinases, p38 and JNK1, in rat follicles maintained in vitro (Tilly et al., 1997b). Collectively, these observations support the concept that sphingomyelinases and ceramide are key components of the somatic cell death program in the ovary (reviewed in Martimbeau and Tilly, 1997), with the latter set of observations in support of recent investigations documenting the central importance of JNK/p38 in mediating ceramide-induced apoptosis resulting from an external cellular stresses (Verheij et al., 1996; Bren-
ner et al., 1997; reviewed in Haimovitz-Friedman et al., 1997a). Lastly, recent work with isolated female germ cells in a paradigm of premature ovarian failure resulting from cancer therapies has provided new evidence regarding the existence and function of sphingolipid molecules in mediating anti-cancer drug-induced oocyte apoptosis (Perez et al., 1997). It was reported that murine oocytes cultured in the presence of therapeutically-relevant doses of doxorubicin (14-hydroxydaunomycin, adriamycin) rapidly exhibit many of the morphologic and biochemical features of apoptosis, including cellular condensation, chromatin cleavage, budding and eventual fragmentation of the dead oocyte into apoptotic bodies of unequal sizes (Tilly et al., 1997a; Perez et al., 1997). Using this model, pretreatment of oocytes with sphingosine1-phosphate, a bioactive lipid molecule produced from ceramide by the sequential actions of ceramidase and sphingosine kinase that is known to interfere with ceramide-promoted stress kinase activation and apoptosis (Cuvillier et al., 1996; reviewed in Spiegel et al., 1996, 1998), was shown to prevent germ cell fragmentation and death induced by anti-cancer drug exposure (Perez et al., 1997). These effects were not mimicked by fumonisinB1, suggesting that drug-induced ceramide generation in this cell lineage is more dependent upon activation of sphingomyelinases as opposed to ceramide synthesis. This is consistent with the finding that, although ceramide synthase is activated in some cell types by daunorubicin (Bose et al., 1995), other cell types can generate ceramide in response to the same drug by sphingomyelinase-dependent mechanisms (Jaffre´zou et al., 1996). In addition, prior activation of protein kinase C in oocytes, using either phorbol 12myristate 13-acetate or a membrane-permeable diacylglycerol analog, provides similar protection from doxorubicin-initiated death (Perez and Tilly, 1998). In light of previous work showing that the diacylglycerol/protein kinase C pathway and the ceramide pathway serve as opposing regulators of cell survival and death in various models of stressinduced apoptosis (Jarvis et al., 1994; Lee et al., 1996; Mansat et al., 1997; reviewed in Haimovitz-
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Friedman et al., 1997b), these latter observations further support the involvement of ceramide as an early signal generated in oocytes following anticancer drug exposure. Future work with mice lacking expression of acid sphingomyelinase should reveal if this enzyme is indeed involved in doxorubicin-stimulated ceramide generation and apoptosis in oocytes, similar to that recently reported for lung endothelial cell death induced by ionizing radiation (Santana et al., 1996b).
4. Conclusions and future directions From the data discussed above, it is clear that progress has been made in elucidating the function of sphingolipid molecules in gamete maturation and death. However, more work is certainly needed to understand the mechanisms underlying the generation and metabolism of lipid second messengers, such as ceramide and sphingosine-1-phosphate, by both somatic and germ cells of the gonads during normal tissue function, as well as during episodes of stress-induced apoptosis caused by pathologic insults. With these data in hand, novel strategies could be developed to enhance the efficiency of gamete maturation and survival needed for optimizing the outcome of various assisted reproductive technologies. Furthermore, selective modulation of the sphingomyelinase or ceramide synthase pathways in germ cells may prove useful for temporarily protecting the ovaries or testes from damage due to conventional cancer therapies, thus enhancing the quality of life in cancer survivors by preserving fertility and normal gonadal function post-therapy. Aside from the importance of further understanding the basic biology of lipid signaling in the ovary and testis, the possibility of fertility manipulation alone warrants future development of these, and as yet undiscovered, applications of sphingolipid research in the context of gonadal development and reproduction.
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Sphingolipid signaling in gonadal development and function Jonathan L. Tilly a,*, Richard N. Kolesnick b a
Vincent Center for Reproducti6e Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Har6ard Medical School, VBK137E-GYN, 55 Fruit Street, Boston, MA 02114, USA b Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Abstract Sphingolipid second messengers, such as ceramide and sphingosine-1-phosphate, signal proliferation, differentiation and death in mammalian cells. The object of this article is to highlight the potential impact of this new information on the study of female and male gonadal development and function. Since the generation of competent gametes by both sexes is precisely regulated by maturational (meiotic) and apoptotic (quality-control) checkpoints, it is proposed that lipid signaling molecules serve as important contributors to the regulation of gametogenesis. The function of sphingolipid molecules in mediating stress- or damage-induced apoptosis in the germ line, an event most-likely associated with impaired gonadal function and infertility, is also discussed. Collectively, these areas represent exciting research directions that may ultimately lead to the development of new therapeutics to coordinate and control fertility in males and females. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Ceramide; Sphingomyelinase; Apoptosis; Germ cell; Oocyte; Sperm; Ovary; Testis
1. Introduction It has been long-recognized that many cell types present in tissues associated with reproduction generate sphingolipid molecules, and in particular ceramide, as mediators or modifiers of hormone action. Only recently, however, has increasing attention been focussed on the function of lipidderived second messengers in modulating apoptosis in reproductive tissues, a research area that has gained considerable notoriety in recent work using a variety of cell lines as well as several * Corresponding author. Tel.: +1-617-7242182; fax: +1617-7267548. E-mail address: [email protected] (J.L. Tilly)
tissues outside of the female and male reproductive systems (reviewed in Spiegel et al., 1996; Haimovitz-Friedman et al., 1997a,b; Spiegel et al., 1998). The purpose of this article is to briefly review the current literature regarding sphingolipid signaling events involved in transducing information provided by external stimuli in cellular development and death in the male and female gonads. This area of investigation represents a new research avenue of considerable significance for both basic biology and clinical medicine since apoptosis in the ovary (reviewed in Tilly et al., 1997a; Tilly, 1998) and testis (reviewed in Dunkel et al., 1997a,b) is central to normal gametogenesis as well as to pathologic gonadal failure. Where appropriate, testable hypotheses will therefore be
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offered as a means to encourage further research into the possible roles of abnormal sphingolipid signaling in the etiology of infertility.
2. Sphingomyelinases and ceramide in gamete maturation Accessory glands of the male reproductive system, such as the seminal vesicles, appear to be major contributors of a number of hydrolytic enzymes, including a cation (cobalt, manganese)sensitive sphingomyelinase, to seminal fluid (reviewed in Vanha-Perttula et al., 1990). The function of these enzymes in semen remains to be fully elucidated, although it has been speculated that hydrolysis of phospholipids on the outer surface of ejaculated male gametes, or perhaps even those present in seminal fluid, may be involved in various sperm functions including capacitation, the acrosome reaction and sperm – egg binding (Vanha-Perttula et al., 1990; Hall et al., 1991). Interestingly, spermatozoa possess high levels of inherent neutral sphingomyelinase activity (Hinkovska et al., 1987), consistent with an earlier study that identified both neutral and acid sphingomyelinase activities in the testis (Spence et al., 1979). It has been recently shown that human sperm maturation during epididymal transport is associated with dramatic changes in the lipid composition of spermatozoal plasma membranes, most notably an increase in phosphatidylcholine with corresponding decreases in phosphatidylserine, phosphatidyl ethanolamine and sphingomyelin (Haidl and Opper, 1997). These findings, taken with the observation that immature and immotile sperm harvested from the caput epididymides gain progressive motility upon phosphatidylcholine exposure in vitro (Haidl et al., 1993), support the hypothesis that a change in sperm plasma membrane lipids, likely mediated at least in part by seminal fluid-derived or intrinsic sphingomyelinase(s), is an important component of male gamete maturation. Additional studies are required, however, to confirm that alterations in spermatozoal plasma membrane content of phosphatidylcholine and/other lipid molecules are in
fact critical for development of sperm motility. In addition, future experiments are needed to assess the functional role of other bioactive sphingolipid molecules known to be present at high levels in the testis, such as sphingosine-1-phosphate (Yatomi et al., 1997), in male gametogenesis and sperm maturation. By comparison, very little is known of the possible function of sphingolipid molecules in female gamete development. The majority, if not all, data available regarding the effects of ceramide and other lipid second messengers in regulating oocyte maturation have been derived from studies of progesterone-induced meiotic cell cycle progression in Xenopus lae6is. For example, induction of H1 kinase activity and germinal vesicle breakdown, two markers of oocyte maturation, can be induced by brief exposure of Xenopus oocytes to bacterial sphingomyelinase (derived from Staphylococcus aureus) in vitro (Strum et al., 1995; Morrill and Kostellow, 1998). These effects can be mimicked by exogenous ceramide or sphingosine, delivered either by inclusion in the culture medium or by microinjection (Strum et al., 1995; Morrill and Kostellow, 1998). Further evidence that these sphingolipid messengers mediate the actions of progesterone, the physiological agent responsible for Xenopus oocyte maturation, is provided by findings of a rapid generation of ceramide in oocytes following progesterone treatment with a concomitant decrease in sphingomyelin content due to activation of a magnesium-dependent neutral sphingomyelinase (Strum et al., 1995; Morrill and Kostellow, 1998). Whether or not a similar role exists for sphingomyelinase-catalyzed ceramide generation in the resumption of meiosis in mammalian oocytes remains to be established.
3. Sphingomyelinases and ceramide in gonadal cell apoptosis Since we are unaware of any published evidence of a direct role for ceramide or sphingosine derivatives in mediating male germ cell death during spermatogenesis or following a pathologic stress to the testis, the majority of this section will
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be devoted to a discussion of the female gonad. However, two studies have provided information that may prove useful for interpreting future experiments on the role of sphingolipid molecules in regulating cell death in the testis (for review of the regulation and significance of apoptosis in the testis, see Dunkel et al., 1997a,b). First, sphingomyelinase has been reported to inhibit basal and gonadotropin-stimulated testosterone production, as well as to decrease gonadotropin binding to its receptor and gonadotropin-promoted cAMP production, in cultured rat Leydig cells (Degnan et al., 1996) Considering the importance, if not the requirement, of androgen biosynthesis by Leydig cells in maintaining spermatogenesis and germ cell survival in the mammalian testis (Tapanainen et al., 1993; Dunkel et al., 1997c; reviewed in Dunkel et al., 1997a,b), these findings suggest that sphingomyelinase-mediated reductions in steroid output within the testis could indirectly lead to excessive spermatogonial and spermatocyte apoptosis. The second report pertaining to the testis is somewhat more indirectly associated with a role for ceramide in male germ cell death, that being the proposed involvement of the Fas – Fas ligand system in deleting germ cells during spermatogenesis in the rat testis (Lee et al., 1997). Since Fas ligation in some (De Maria et al., 1998), but not all (Watts et al., 1997; Hsu et al., 1998), cell types is known to cause an elevation in intracellular ceramide levels as a potential mediator of apoptosis induced by this cytokine, it is possible that activation of Fas-mediated death in male germ cells is transduced via the ceramide pathway. Moreover, data provided by Lee et al. (1997) also showed that significant numbers of male germ cells become Fas-positive, and in turn more sensitive to Fas ligand-induced apoptosis, in response to treatment of rats with biohazardous chemicals. Assuming the involvement of ceramide in this paradigm of testicular cell death as well, these findings, which implicate the Fas pathway as a ‘sensor’ of toxicant-induced testicular damage, would be in agreement with previous data linking ceramide to apoptosis induced by a variety of physiologic and pathologic stressors (Verheij et al., 1996). These hypotheses regarding the poten-
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tial involvement of ceramide in Fas-mediated male germ cell death, however, await testing in future investigations. The direct involvement of sphingomyelinasegenerated second messengers in mediating cellular function, and more recently cellular life and death decisions, in the female gonad is somewhat more defined (for review of apoptosis in the ovary, see Marita and Tilly, 1999; Tilly and Robles, 1999). One of the earliest reports of a function for sphingolipid molecules in the ovary proposed a role for ceramide as being responsible for the inhibitory actions of tumor necrosis factor alpha (TNFa) on gonadotropin-promoted aromatase activity, and hence estradiol biosynthesis, in cultured rat granulosa cells (Santana et al., 1995). In addition to showing that both bacterial sphingomyelinase and a short-chain membrane-permeable analog of ceramide (N-acetylsphingosine) could mimic the effects of TNFa, these authors also demonstrated a rapid decrease in sphingomyelin with a corresponding elevation in endogenous ceramide in TNFa-treated granulosa cells. This study was shortly followed by a comparable series of investigations on the role of sphingomyelin hydrolysis and the ensuing generation of ceramide as effectors of interleukin-1 beta (IL1b)-regulated steroid and prostaglandin production in cultured granulosa cells (Santana et al., 1996a). Although these two papers clearly demonstrated that ovarian follicular granulosa cells possess a hormonally-modulated sphingomyelinase activity and are capable of generating ceramide as a second messenger, it remained to be established whether or not these early signaling events also participated in determining granulosa cell fate. A comprehensive series of experiments by Witty et al. (1996) then clearly established a connection between ceramide and apoptosis induced in avian ovarian granulosa cells by either serum-starvation or exposure to acute pathologic stress. In the case of tropic hormone deprivation-induced apoptosis, a membrane-permeable ceramide analog was found to further exacerbate basal levels of granulosa cell death as well as completely override the survival actions of a cAMP analog. Moreover, apoptosis initiated in granulosa cells as a result of exposure to a common anti-cancer drug (i.e.
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daunorubicin), but not to ultraviolet (UV) irradiation, could be completely suppressed by pretreating the cells with the ceramide synthase inhibitor, fumonisin-B1 (Witty et al., 1996). These latter observations fully support a previous report using fumonisin-B1 in a human leukemia cell line that first proposed a role for de novo ceramide synthesis as a novel effector of apoptosis in cancer cells treated with chemotherapeutic drugs (Bose et al., 1995). Additionally, the inability of fumonisin-B1 to protect granulosa cells from apoptosis caused by UV irradiation is similar to published data identifying a requirement for acid sphingomyelinase (as opposed to ceramide synthase) in ceramide generation required for radiation-induced apoptosis in lung endothelial cells (Santana et al., 1996b) and in UV-induced activation of c-Jun N-terminal kinase (JNK) (Huang et al., 1997). This work with avian granulosa cells (Witty et al., 1996) was paralleled by studies with rat ovarian follicles maintained in vitro, in which membrane-permeable ceramide analogs were shown to both accelerate basal apoptosis in cultured follicles (Tilly et al., 1996) and to completely antagonize gonadotropin-promoted follicular cell survival (Kaipia et al., 1996). Studies of the rat ovary have further indicated that the second functionally-important somatic cell lineage of the ovarian follicle, theca-interstitial cells, also appear to possess a cytokine-activated signal transduction pathway coupled to ceramide-induced apoptosis (Foghi et al., 1998). Additionally, endogenous ceramide levels are elevated in cultured rat ovarian follicles at a time associated with the onset of apoptosis in this model (Tilly et al., 1997b), and exogenous ceramide analogs have been reported to rapidly induce activation of the stress-related kinases, p38 and JNK1, in rat follicles maintained in vitro (Tilly et al., 1997b). Collectively, these observations support the concept that sphingomyelinases and ceramide are key components of the somatic cell death program in the ovary (reviewed in Martimbeau and Tilly, 1997), with the latter set of observations in support of recent investigations documenting the central importance of JNK/p38 in mediating ceramide-induced apoptosis resulting from an external cellular stresses (Verheij et al., 1996; Bren-
ner et al., 1997; reviewed in Haimovitz-Friedman et al., 1997a). Lastly, recent work with isolated female germ cells in a paradigm of premature ovarian failure resulting from cancer therapies has provided new evidence regarding the existence and function of sphingolipid molecules in mediating anti-cancer drug-induced oocyte apoptosis (Perez et al., 1997). It was reported that murine oocytes cultured in the presence of therapeutically-relevant doses of doxorubicin (14-hydroxydaunomycin, adriamycin) rapidly exhibit many of the morphologic and biochemical features of apoptosis, including cellular condensation, chromatin cleavage, budding and eventual fragmentation of the dead oocyte into apoptotic bodies of unequal sizes (Tilly et al., 1997a; Perez et al., 1997). Using this model, pretreatment of oocytes with sphingosine1-phosphate, a bioactive lipid molecule produced from ceramide by the sequential actions of ceramidase and sphingosine kinase that is known to interfere with ceramide-promoted stress kinase activation and apoptosis (Cuvillier et al., 1996; reviewed in Spiegel et al., 1996, 1998), was shown to prevent germ cell fragmentation and death induced by anti-cancer drug exposure (Perez et al., 1997). These effects were not mimicked by fumonisinB1, suggesting that drug-induced ceramide generation in this cell lineage is more dependent upon activation of sphingomyelinases as opposed to ceramide synthesis. This is consistent with the finding that, although ceramide synthase is activated in some cell types by daunorubicin (Bose et al., 1995), other cell types can generate ceramide in response to the same drug by sphingomyelinase-dependent mechanisms (Jaffre´zou et al., 1996). In addition, prior activation of protein kinase C in oocytes, using either phorbol 12myristate 13-acetate or a membrane-permeable diacylglycerol analog, provides similar protection from doxorubicin-initiated death (Perez and Tilly, 1998). In light of previous work showing that the diacylglycerol/protein kinase C pathway and the ceramide pathway serve as opposing regulators of cell survival and death in various models of stressinduced apoptosis (Jarvis et al., 1994; Lee et al., 1996; Mansat et al., 1997; reviewed in Haimovitz-
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Friedman et al., 1997b), these latter observations further support the involvement of ceramide as an early signal generated in oocytes following anticancer drug exposure. Future work with mice lacking expression of acid sphingomyelinase should reveal if this enzyme is indeed involved in doxorubicin-stimulated ceramide generation and apoptosis in oocytes, similar to that recently reported for lung endothelial cell death induced by ionizing radiation (Santana et al., 1996b).
4. Conclusions and future directions From the data discussed above, it is clear that progress has been made in elucidating the function of sphingolipid molecules in gamete maturation and death. However, more work is certainly needed to understand the mechanisms underlying the generation and metabolism of lipid second messengers, such as ceramide and sphingosine-1-phosphate, by both somatic and germ cells of the gonads during normal tissue function, as well as during episodes of stress-induced apoptosis caused by pathologic insults. With these data in hand, novel strategies could be developed to enhance the efficiency of gamete maturation and survival needed for optimizing the outcome of various assisted reproductive technologies. Furthermore, selective modulation of the sphingomyelinase or ceramide synthase pathways in germ cells may prove useful for temporarily protecting the ovaries or testes from damage due to conventional cancer therapies, thus enhancing the quality of life in cancer survivors by preserving fertility and normal gonadal function post-therapy. Aside from the importance of further understanding the basic biology of lipid signaling in the ovary and testis, the possibility of fertility manipulation alone warrants future development of these, and as yet undiscovered, applications of sphingolipid research in the context of gonadal development and reproduction.
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