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Endocrinology Vol. 141, No. 6 2027-2032
Copyright © 2000 by The Endocrine Society

ARTICLES

Prolactin Induces Apoptosis in the Penultimate Spermatogonial Stage of the Testes in Japanese Red-Bellied Newt (Cynops pyrrhogaster)1

Takashi Yazawa, Takashi Yamamoto and Shin-Ichi Abé

Department of Materials and Life Science, Graduate School of Science and Technology, Kumamoto University, Kurokami 2–39-1, Kumamoto 860-8555, Japan

Address all correspondence and requests for reprints to: Shin-Ichi Abé, Department of Materials and Life Science, Graduate School of Science and Technology, Kumamoto University, Kurokami 2–39-1, Kumamoto 860-8555, Japan. E-mail: abeshin{at}gpo.kumamoto-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Cell death is a common feature during spermatogenesis and, in some seasonal breeding animals, is often observed at the transition stage from spermatogonia to spermatocytes. In the Japanese red-bellied newt, we have previously shown that this cell death is caused by the elevated titer of plasma PRL that occurs after animals are transferred to low temperature, suggesting that cell death causes the cessation of spermatocytogenesis from late autumn to early spring. In the present report, first we show that the injection of PRL into newts causes apoptosis in spermatogonia after the sixth mitotic division, the penultimate one before spermatogonia normally enter meiosis. Second, we demonstrate in organ cultures of testes fragments that PRL acts directly on the testes. Third, we show that the action by PRL is inhibited by FSH dose dependently.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
APOPTOSIS is a mechanism of cell destruction used by multicellular organisms to remove cells that are superfluous, abnormal, or no longer needed (1, 2, 3). In the case of germ cells, many developing ones in both vertebrates and invertebrates are lost as a result of apoptosis (4, 5, 6). Roosen-Runge (7) reported that cell death is a common feature in spermatogenesis and occurs exclusively or preferentially in certain developmental stages, though species specific in quality and quantity. For example, in some vertebrates, spermatogonia are the most commonly observed dead cells in testes (8, 9, 10). However, the physiological significance and the mechanisms responsible for apoptosis in germ cells are not fully understood.

Degeneration of spermatogenic cells at the transition stage from spermatogonia to spermatocytes is frequently observed in seasonal breeding animals (11, 12, 13, 14, 15). In the crested newt, administration of ovine PRL induces spermatogonial cell death, but coinjection of FSH prevents it (16, 17). In the Japanese red-bellied newt, this degeneration occurs following the elevated titer of plasma PRL which occurs after animals are transferred to low temperature, suggesting that this cell death causes the cessation of spermatocytogenesis (disappearance of spermatocytes by spermatogonial cell death) from late autumn to early spring (18).

The urodele testis displays well-marked zones of spermatogenic cell types because lobules formed at the cephalic region gradually acquire more caudal positions as the cells mature (19). When longitudinal sections of newt testis are made, all spermatogenic stages from spermatogonia to the most advanced stage for the season can be observed. Thus, the newt testis is ideal for studying the mechanism and significance of cell death in the seasonal breeder. Here, we present the following findings: apoptosis by PRL occurs only in the penultimate mitotic generation of spermatogonia, PRL acts directly on testes, and FSH counteracts the action of PRL in vitro.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Adult male newts, Cynops pyrrhogaster, were purchased from a dealer (Hamamatsu Seibutsu Kyozai Ltd., Hamamatsu, Japan), kept at 22 C under 12-h light, 12-h dark illumination and fed frozen Tubifex.

Counting the number of germ cells in a spermatocyst
Testes were fixed in Bouin’s solution, dehydrated in graded ethanol, embedded in paraffin, and sectioned serially at 5 µm thickness. The sections were stained with hematoxylin-eosin. To estimate the number of germ cells (N) in a given spermatocyst, Abercrombie’s formula (20) was used: N = n x 5/(5 + d) where n = number of nuclei in a given cyst on a section and d = average diameter of nuclei.

Treatment with PRL and FSH
Thirty males were divided into three groups. Each group was administered injections of saline (100 µl), 25 IU ovine PRL (Sigma, St. Louis, MO), or 25 IU ovine PRL plus 500 µg porcine FSH (Sigma) every other day during 4 days (two injections in total). Forty-eight hours after the last injection, the newts were anesthetized, the testes were excised and fixed in Bouin’s solution.

DNA analysis
DNA extraction was performed as described by Tilly and Hsueh (21). Three micrograms of DNA were loaded onto a 2.5% agarose gel and stained with ethidium bromide.

In situ DNA 3'-end labeling (TUNEL method)
Testes were fixed in Bouin’s solution and routinely processed for paraffin embedding and sectioning. The sections were stained with an Apop Tag In situ Detection Kit (Oncor) according to manufacturer’s instructions and counterstained with hematoxylin.

Organ culture of testicular fragments
Newts were transferred from cold room to room temperature and kept for 3–4 weeks with feeding until operation. During that time, spermatogonia proliferated and then active spermatocytogenesis occurred. At the operation, apical parts of the testes was cut off, so that younger generation of spermatogonia was not included in the culture fragments. The rest of the testes was cut into fragments (about 2 x 2 mm) longitudinally in a cephalo-caudal plane. By this procedure, many testes fragments each containing spermatogonia-spermatocytes zone were obtained.

The fragments were placed on a float of nuclepore filter (three pieces; Coaster Corp., Cambridge, MA) in a 35-mm plastic dish (Falcon, Lincoln Park, NJ; 1008). These testicular fragments were cultured for 12–48 h at 22 C in humidified air. The basal culture medium consists of Leibovitz L-15 medium supplemented with 10 mM HEPES, adjusted to pH 7.4 with 1 N NaOH.

Estimation of spermatogonial cell death
Testis fragments before and after culture were fixed in Bouin’s solution. To estimate the cell death index for spermatogonia, three random sections stained with hematoxylin-eosin from each of three cultured testis fragments were examined, and the number of cysts containing degenerated spermatogonia was counted. The results were expressed as the percentage of cysts containing degenerated spermatogonia per total cysts of spermatogonia comprising 26 germ cells.

Statistics
Cell death indices were analyzed by the Student’s t test. A probability level of <0.05 indicated a statistically significant difference.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PRL induces apoptosis in spermatogonia in vivo
Ip injection of ovine PRL in newts induced pyknotic degeneration of spermatogonia in cysts adjacent to lobules containing spermatocyte stage, whereas injection of saline had little, if any, effect (Fig. 1Go). All spermatogonia in a given cyst died simultaneously; however, the nuclei of Sertoli cells appeared unaffected. Also, spermatogonia in earlier stages as well as primary spermatocytes seemed unaffected by PRL. The simultaneous injection of FSH with PRL antagonized the degenerative effect by PRL (data not shown). These results are consistent with those obtained in crested newts by Mazzi and Vellano (17) and Mazzi et al. (16).



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  		Figure 1. Photomicrographs showing (A) control testes in the secondary spermatogonia-primary spermatocytes stage, (B) PRL-induced apoptosis in secondary spermatogonia, and (C) apoptosis in secondary spermatogonia detected by the TUNEL method. Ten newts each were injected with either saline (100 µl) or 25 IU of ovine PRL every other day during 4 days; 48 h after the last injection the testes were excised and fixed in Bouin’s solution. PC, Primary spermatocytes: SG, secondary spermatogonia. Arrow, Sertoli cell’s nucleus. Arrowheads, Apoptosis-induced secondary spermatogonia detected by TUNEL method. Scale bar, (A) and (B), 50 µm: (C), 10 µm.

 
To determine whether PRL injections induce apoptosis in newt testes, we examined by electrophoresis and the TUNEL method if DNA fragmentation occurred. DNA isolated from testes of newts injected with PRL displayed a ladder profile with various molecular sizes, whereas that isolated from testes of saline-injected newts showed only high molecular weight DNA (Fig. 2Go). In addition, most, if not all, of the degenerated nuclei in the late spermatogonial stage were TUNEL-positive (Fig. 1CGo). Thus, PRL induces apoptosis in spermatogonia just before meiosis.



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  		Figure 2. Electrophoresis showing DNA fragmentation in testis induced by PRL. (-) control testes: (+) testes from PRL-injected newts. DNA from whole testis was extracted and 3 µg were loaded onto an agarose gel.

 
PRL induces the death of spermatogonia after the 6th division, whereas normally they undergo 7 mitotic divisions before entering meiosis
As in other anamniote species, spermatogenesis in urodeles occurs within spermatocysts comprising germ cells and Sertoli cells (19). Within each cyst, germ cells develop synchronously. This feature permits us to estimate the number of mitotic divisions that spermatogonia undergo before entering meiosis by counting the number of primary spermatocytes per cyst (Fig. 3Go). We found that most cysts contained 27 primary spermatocytes, though a few cysts comprised 26 primary spermatocytes. Thus, we conclude that each primary spermatogonium undergoes 7 mitotic divisions in a cyst before entering meiosis.



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  		Figure 3. Histogram of cysts comprising primary spermatocytes (white column) and of cysts comprising secondary spermatogonia in the same lobule which contain degenerative cysts (shaded column).

 
With respect to the degenerated cysts, we observed that they were localized in lobules located at a boundary between zones of spermatogonia and spermatocytes. This observation suggested to us that PRL caused cell death in a stage-specific manner. However, we could not directly answer this question by counting nuclei in degenerated cysts, because some degenerated germ cells could have been phagocytosed by Sertoli cells. Instead, we counted the number of living germ cells in the neighboring cysts in the same lobule, as the number of germ cells/cyst was almost the same in a lobule. We found that most cysts neighboring the degenerative cysts contained 26 germ cells (Fig. 3Go). Thus, we concluded that PRL induced apoptosis in spermatogonia after the 6th division.

PRL induces apoptosis in spermatogonia by direct action on testes
Testes fragments in culture were exposed to PRL (5 µg/ml of medium) to determine whether PRL exerts direct action on testes. By 24 h over 15% of the spermatogonia degenerated, and this percentage increased to more than 40% by 48 h, whereas degeneration of germ cells in the control medium (less than 15%) proceeded very slowly (Fig. 4Go). As in vivo, spermatogenic stages other than late spermatogonia appeared unaffected by PRL.



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  		Figure 4. Percentage of apoptosis occurring in the penultimate generation of spermatogonia during culture in control medium (white squares), in medium containing FSH (1 µg/ml; open circles), PRL (5 µg/ml; black squares), or PRL (5 µg/ml) + FSH (1 µg/ml) (black circles). Each point represents the mean ± SEM of triplicate cultures. *, Significantly different from the control values (P < 0.05).

 
FSH antagonizes the effect of PRL in vitro
In previous studies FSH was shown to stimulate the viability and proliferation of spermatogonia and their differentiation into primary spermatocytes in vivo (22) and in vitro (23, 24, 25). Those results suggested to us that FSH and PRL have opposite effects on spermatogonia. Indeed, this is true. The addition of FSH to the basal media or to media containing PRL significantly inhibited the degeneration of spermatogonia (Fig. 4Go). This finding was further supported by experiments in which the concentration of one hormone was kept constant while that of the other hormone was varied (Fig. 5Go). Spermatogonial degeneration increased linearly with increased concentration of PRL (up to 5 µg/ml) in the presence of FSH (1 µg/ml) (Fig. 5AGo). On the other hand, FSH inhibited PRL action (5 µg/ml) in a dose-dependent manner (Fig. 5BGo). Thus, FSH and PRL when present together are antagonists.



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  		Figure 5. Counteraction between FSH and PRL in the induction of apoptosis in spermatogonia. Percentage of apoptosis after culture (2 days) in a medium with (A) varying concentrations of PRL with constant concentration of FSH (1 µg/ml), and with (B) varying concentrations of FSH with constant concentration of PRL (5 µg/ml). Each bar represents the mean ± SEM of triplicate cultures.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we have shown that PRL induces apoptosis in newt spermatogonia. This is, as far as we know, the first report that demonstrated that PRL induces apoptosis in germ cells or any type of cells among vertebrates. One of our goals is to understand the mechanism of apoptosis during urodele spermatogenesis. To this end, we showed above that (1) PRL induces apoptosis at a specific time, namely, in secondary spermatogonia after their penultimate mitosis before meiosis; (2) PRL acts directly on testes; and (3) the action of PRL is inhibited by FSH.

Previous observations revealed that cell death occurs in the testes of various species (7) including newts (14) when the ambient temperature lowers naturally, and PRL was associated with various reproductive phenomena in urodeles such as adaptation to reproductive environment, sexual behavior, development of reproductive organs and sexual characters (26, 27, 28, 29). However, the effect of PRL to cause cell death was reported only by Mazzi and colleagues (16, 17) and recently by us (18). In this latter report, we showed that spermatogonial cell death is induced when newts are incubated at low temperatures (12 and 8 C) but not at high temperatures (18 and 22 C). Also, we demonstrated that cell death is induced by the elevated titer of plasma PRL caused by low temperature. This conclusion was supported by the fact that anti-PRL antibody injections completely suppressed cell death for as long as 3 days (18). In our present report, we directly showed in vitro that the decision for the life or death of spermatogonia is regulated by the FSH/PRL ratio, consistent with a previous in vivo observation (16, 17). The preceding studies in urodeles permit the following interpretation of the physiological events occurring in vivo. In the spring when the temperature rises, the FSH/PRL concentration ratio in the plasma increases because the PRL secreted by the pituitary is reduced, preventing spermatogonial death and permitting them to proliferate and differentiate into primary spermatocytes. On the other hand, in late fall, when the ambient temperature lowers, the FSH/PRL ratio also decreases because PRL secreted from the pituitary increases, causing spermatogonial death and cessation of spermatocytogenesis. Yet to be explained is whether or not FSH secretion from the pituitary and testis sensitivity to FSH and/or PRL are dependent on temperature.

Other observations made in sharks, newts, frogs, birds and mammals further document spermatogonial cell death and also indicate hormonal involvement in the process. In the dogfish (Squalus acanthias) germ cell degeneration occurs in the ampullae between spermatogonia and spermatocytes in the spring before spermatogenesis, and the degenerative bands can be induced by removal of the ventral lobe of the pituitary in Scyliorhinus canicula (L.) (12). The fact that the zone of degeneration appears seasonally or after hypophysectomy at the transition from secondary spermatogonia to spermatocytes (13) suggests that the rate of cyst degeneration is hormonally controlled (30). Also, in the common frog (Rana temporaria) cessation of spermatocytogenesis occurs in early spring when spermatogonia proliferate (11). It is not clear in these species whether PRL is involved in spermatogonial death and whether PRL secretion depends on ambient temperature.

Also, PRL has an antigonadal effect in avian species. In pigeons (31) and cocks (32), injection of PRL induces, as in newts, testis regression, and FSH counteracts it. In the European starling, Dawson and Sharp (33) suggested that the seasonal photo-induced increase in PRL accelerates gonadal regression during the onset of photorefractoriness. In this regard, suppression of PRL secretion by ergot compounds delays the long day-induced gonadal regression in mammals [blue fox (34) and red deer (35)]. Also, in the newt, ergot compounds inhibit cessation of spermatocytogenesis under moderately low temperature condition (our unpublished results). The results in these various species indicate that PRL may be involved in causing testis regression by inducing apoptosis in germ cells.

On the other hand, PRL is reported to stimulate cell proliferation and abrogate apoptosis. In frogs, PRL has larval growth-promoting activity (36) and antimetamorphic activity; administration of PRL to metamorphosing tadpoles blocks tail resorption that is a result from apoptosis in muscles and connective tissues (37). PRL increases epidermal mitotic activity in both intact and hypophysectomized newts (Notophthalmus viridescens viridescens) (38), though it is uncertain whether PRL acts directly on the epidermis or not. PRL stimulates proliferation in human prostate cancer cell lines (39) and Nb2 lymphoma cell line (40). Future studies of intracellular signaling pathways will elucidate how PRL induces apoptosis in newt testes, while it stimulates proliferation in other systems.

How does FSH counteract apoptotic action by PRL in the newt spermatogonia? Relevant to this question are the studies of Nb2 lymphoma cells in which dexamethasone (Dex) causes a concentration-dependent inhibition of PRL-stimulated proliferation, whereas PRL causes, in the presence of Dex, a concentration-dependent inhibition of cytolysis without changing cell number (41). Their work indicates that PRL and Dex act on the cells through its specific receptors, PRL receptor (PRLR) and glucocorticoid receptor, respectively. Our present study seems much more complex than theirs: we showed in organ and reconstituted cultures that FSH promotes the survival and proliferation of spermatogonia and their differentiation into primary spermatocytes via Sertoli cells (23, 24, 25), and that FSH binds to Sertoli cells but not to germ cells (42). Thus, Sertoli cells probably produce one or more factors that may stimulate spermatogonia. However, it remains unknown whether PRL mediates its action directly on spermatogonia or indirectly through Sertoli cells. Further study is required to elucidate whether PRL causes apoptosis in spermatogonia directly or not.

Finally, why does PRL induce apoptosis only in the penultimate generation of spermatogonia? One needs to speculate on possible controls responsible for the temporal and cell-type specificity of apoptosis. One possibility is that PRLR might be expressed only in spermatogonia at penultimate stage. Another possibility is that PRLR is present at all stages, but components of the intracellular signaling system involving PRL-PRLR might differ in the late spermatogonial stage from those in other stages. For example, members of the caspase family known to execute apoptosis might be involved only in late spermatogonia, whereas those of the Bcl-2 family (Bcl-2, Bcl-xL, and Bcl-w) or IAP family known to inhibit apoptosis might be absent (43, 44, 45).

Future studies focused on the molecular components acting in the apoptosis pathway induced by PRL in newt spermatogonia should elucidate the mechanisms controlling this cell-specific and stage-specific apoptosis during spermatogenesis.


   Acknowledgments
 
We thank Prof. Marie A. DiBerardino for critical reading and editing the manuscript.


   Footnotes
 
1 This work was supported by Grants-in-Aid for Scientific Research (no. 09480206) and Priority Areas (no. 07283104) from the Ministry of Education, Science, Sports and Culture of Japan. Back

Received January 12, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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