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Sertoli Cell Proliferation during Prepubertal Development in the Rhesus Monkey (Macaca mulatta) Is Maximal during Infancy when Gonadotropin Secretion Is Robust

Departments of Cell Biology, Physiology (D.R.S., T.M.P.), and Medicine (G.R.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Dr. Tony M. Plant, University of Pittsburgh School of Medicine, Department of Cell Biology and Physiology, S-828A Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261. E-mail: plant1{at}pitt.edu.

	Abstract

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Although a marked pubertal increase in Sertoli cell number is a hallmark of testicular development in the rhesus monkey, the ontogeny of this somatic cell type before puberty is less clear. To clarify this issue, groups (n = 4) of neonate (1–2 d old), infant (4–5 months old), juvenile (14–17 months old), and adult male rhesus monkeys were injected with 5-bromo-2'-deoxyuridine (BrdU) 2 h before castration. Tissue was fixed in Bouin’s fluid, and the percentage of BrdU-labeled Sertoli cells at each developmental stage was calculated. In addition to the labeling index, Sertoli cell number per testis for the neonate and infant groups was enumerated using standard histomorphometry and compared with that previously reported by this laboratory for juvenile and adult rhesus monkeys. The number of Sertoli cells per testis in infants (156 ± 49 x 10⁶, mean ± SD) was 4-fold greater than that in neonates (42 ± 12 x 10⁶). The previously established value for this parameter in juvenile monkeys was 286 ± 121 x 10⁶. Incorporation of BrdU into nuclei of Sertoli cells indicated that these cells were mitotically active at all three stages of prepubertal development. The labeling index in the neonate and infant groups (1.33% in both cases), however, was significantly greater than that in juveniles (0.25%). From the foregoing results, we conclude that Sertoli cell proliferation during prepubertal development in the rhesus monkey occurs predominantly during infancy, when gonadotropin secretion is elevated, and to a lesser extent during the juvenile phase of development, when circulating gonadotropin concentrations are undetectable.

	Introduction

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THE NUMBER OF Sertoli cells in the adult testis is recognized to be a major determinant of sperm output (1, 2). In higher primates, two distinct periods of Sertoli cell proliferation have been described: the first beginning in fetal life and continuing throughout the prepubertal period, and the second occurring at puberty when spermatogenesis is initiated (3, 4). The second, or pubertal, phase of primate Sertoli cell division is observed in association with the rise in gonadotropin secretion that occurs at this stage of development and, in the juvenile rhesus monkey, may be induced precociously by the premature activation of endogenous LH and FSH secretion (4). The role of the gonadotropic hormones in stimulating Sertoli cell proliferation during the prepubertal phase of primate development is less clear, but two schemata of proliferation have been proposed (5). In the first, prepubertal proliferation of this somatic cell type is posited to be also gonadotropin dependent, and therefore to be restricted to the first 6 months of postnatal life (infancy), a period of development, which, like that of puberty, is characterized by robust LH and FSH secretion (6). In the second model, Sertoli cell division before puberty is argued to be gonadotropin independent and therefore to occur insidiously and at a relatively constant rate throughout both infancy and the protracted and relatively hypogonadotropic juvenile phase of development that, in higher primates, separates infancy from puberty (6).

The objective of this study was to determine which of the foregoing schemata best describes the prepubertal pattern of Sertoli cell proliferation in the rhesus monkey and to relate this aspect of testicular ontogeny to that previously established for the pubertal phase of development (4). To this end, Sertoli cell number in the testis of 1- to 2-d-old (neonate) and 4- to 5-month-old (infant) male rhesus monkeys were enumerated and compared with the value for this parameter previously reported by our laboratories for 15- to 17-month-old juvenile monkeys (4). If Sertoli cell proliferation before puberty is gonadotropin dependent, it was predicted that 1) the number of these cells in the testes from infants would be noticeably greater than that in newborn neonates because the testis would have been subjected to gonadotropin stimulation between these two phases of early postnatal development, and 2) that the number of Sertoli cells in the testis from the infants would be similar to that previously reported for juvenile monkeys because of the hiatus in gonadotropin secretion that spans these developmental stages (6). In addition, 5-bromo-2'-deoxyuridine (BrdU) was injected iv before castration in the newborn and infant monkeys, and also in a group of juvenile and adult monkeys, to obtain a direct index of Sertoli cell mitosis at these critical stages of development.

	Materials and Methods

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Animals and tissue preparation

Sixteen male rhesus monkeys born at the Primate Core of the Center for Research in Reproductive Physiology and ranging in age from 1 d to 12 yr were used. Neonate (1–2 d of age, 0.5–0.7 kg body weight) and infant monkeys (4–5 months of age, 1.2–1.4 kg body weight) were housed with their mothers in single cages. Juvenile (14–17 months of age, 2.6–3.2 kg body weight) and adult (6–12 yr of age, 9.5–13.5 kg body weight) animals were caged individually. All monkeys were maintained under a controlled photoperiod (lights on 0600–1800 h), as described previously (7) in accordance with NIH Guidelines for the Care and Use of Experimental Animals.The experimental procedures were approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

Neonates, infants, adults, and one juvenile were sedated with ketamine hydrochloride (20 mg/kg body weight im; Ketaset, Fort Dodge Laboratories, Fort Dodge, IA), and an iv bolus of BrdU (33 mg/kg body weight as a 2% solution in PBS, Sigma Chemical Co., St. Louis, MO) was injected. The remaining three juveniles were injected with BrdU via chronic indwelling venous catheters. Two hours later, the animals were orchidectomized using sterile technique. For this purpose, the neonates and infants were anesthetized with ketamine hydrochloride (50–100 mg/kg body weight). In most instances, juveniles and adults were anesthetized with 1.5–2.5% isoflurane in oxygen after sedation with ketamine hydrochloride. One juvenile, however, was anesthetized with sodium pentobarbital (25 mg/kg body weight iv, Nembutal sodium solution, Abbott Laboratories, North Chicago, IL). The testis was weighed, and those from the three prepubertal groups were bisected perpendicular to the long axis of the testis. The larger adult testes were cut into several pieces. One half of a testis from each neonate, infant, and juvenile monkey and several pieces from one testis of each adult were fixed overnight in Bouin’s solution.

Postoperatively each monkey received antibiotic and analgesics as appropriate.

Morphometric analysis

Testicular tissue was dehydrated and embedded in paraffin. Fifty consecutive 5-µm sections were cut from each half testis of the neonates and infants. Every 10th section was stained with periodic acid-Schiff (Sigma Chemical Co.) and hematoxylin (Gill No.3, Sigma Chemical Co.) for morphometric analyses. The total number of Sertoli cells per testis and the volume fraction, absolute volume, diameter, and length of the seminiferous cords were calculated as previously described (4).

BrdU immunocytochemistry and labeling index

BrdU was immunocytochemically identified using a modification of the method described by Okano et al. (8). For this purpose, the 9th and 49th sections of a sequential series of 5-µm sections from a testis of each neonate, infant, and juvenile, and one 5-µm section from two randomly selected pieces of testicular tissue from each adult monkey were incubated in a solution of equal parts formamide and 2x saline sodium citrate buffer at 62 C for 5 h. Sections were transferred to 2 N HCl at 37 C for 1 h. After repeated washing with borate buffer (pH 8) followed by PBS, sections were incubated at 4 C for 3 d with anti-BrdU antibody (mouse IgG monoclonal antibody, Roche Diagnostic Corp., Indianapolis, IN) diluted 1:167 in 50 mM PBS containing 0.05% Triton and 1% normal horse serum. After several rinses with PBS, sections were incubated at room temperature with biotinylated horse antimouse antiserum (diluted 1:200 in PBS/Triton and 1% normal horse serum) for 1 h. After rinsing, sections were placed in a solution of an avidin-horseradish peroxidase complex (Vectastain ABC Elite Kit, Vector Laboratories Inc., Burlingame, CA) for 1 h at room temperature. Horseradish peroxidase was visualized with 3,3'-diaminobenzidine [Sigma Chemical Co.; 0.5 mg/ml in 50 mM Tris buffer (pH 7.6)]. A dark brown precipitate indicated the presence of BrdU. Sections were then counterstained using periodic acid-Schiff and hematoxylin. The Sertoli cell labeling index for each animal was determined by counting the number of BrdU-labeled Sertoli cells, divided by the total number of Sertoli cells in the two sections. For this purpose, each section was examined by moving the microscope stage in a systematic pattern to ensure that no seminiferous cord profile was evaluated twice. As a cross-section of cord came into the microscope field, each Sertoli cell nucleus was counted and scored for BrdU labeling. The labeling index equals the number of BrdU-labeled Sertoli cells divided by the total number of this cell type. Approximately 3000–4600 Sertoli cells per animal were evaluated at each developmental stage to derive the labeling index.

Statistical analysis

All numerical data are expressed as mean ± SD. The significance of differences between the mean number of Sertoli cells per testis of the neonates and infants was compared using Student’s t test. The significance of differences in mean BrdU labeling indexes was determined using a one-way ANOVA followed by the Newman-Keuls test for multiple comparisons (9). In all cases, significance was assigned at P 0.05.

	Results

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Testicular morphology and morphometry

The mean testicular weight, and volume fraction, absolute volume, and length of the seminiferous cords of the testis of infants were significantly greater than those of neonates. The mean diameter of the seminiferous cords at these two developmental phases, however, was not different (Table 1).

View larger version (142K): [in this window] [in a new window]   FIG. 1. Photomicrographs of testes of 1- to 2-d-old (neonate, A and C) and 4- to 5-month-old (infant, B and D) rhesus monkeys. Panels A and B show equatorial cross-sections of testes at the same magnification, illustrating developmental differences in size and parenchyma. Panels C and D show details of seminiferous cord cross-sections containing only Sertoli cells (SC) and type A pale and type A dark spermatogonia (Ap and Ad, respectively). Sertoli cells were immature and contained an ovoid nucleus with one or more nucleoli, associated with a few heterochromatic clumps. Spermatogonia were generally near the basement membrane. MT, Mediastinum testis. Scale bar, 20 µm.

View larger version (19K): [in this window] [in a new window]   FIG. 2. Number of Sertoli cells per testis (mean ± SD) from 1- to 2-d-old (neonate) and 4- to 5-month-old (infant) rhesus monkeys. *, Significantly greater.

BrdU-labeled cells were observed in the testes of neonate, infant, juvenile, and adult monkeys (Fig. 3); labeled Sertoli cell nuclei, however, were observed only at the three stages of prepubertal development (Fig. 3). As shown in Fig. 4, the mean labeling index of Sertoli cells of neonates and infants was comparable (1.3%), and both were significantly greater than that of the juveniles (0.25%).

View larger version (148K): [in this window] [in a new window]   FIG. 3. Photomicrographs of testis of neonate (A), infant (B), juvenile (C), and adult (D) monkeys that were injected iv with BrdU 2 h before castration. Nuclei incorporating BrdU are dark brown. Labeled Sertoli cells in neonate, infant, and juvenile testes (A–C) are indicated by the yellow arrows. It should be noted that Sertoli cells in adults (D, black arrow) were not observed to be labeled. In panels B and D, labeled spermatogonia are also shown (white arrows). Scale bar, 20 µm.

View larger version (19K): [in this window] [in a new window]   FIG. 4. Labeling index of Sertoli cells in the testes of neonate (N; 1–2 d old), infant (I; 4–5 months old), juvenile (J; 14–17 months old), and adult (A) rhesus monkeys (n = 4 in each group). Bars with the same letter are not significantly different from each other.

	Discussion

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Studies of Sertoli cell proliferation in the rodent have revealed labeling indexes during the first 2 wk of life of approximately 20% (10, 12, 13). This contrasts with a labeling index of 1.3% in neonate and infant monkeys observed in the present study and suggests that the duration of the cell cycle of the monkey Sertoli cell is markedly longer than that in the rat. The alternative possibility, that the population of Sertoli cells in the prepubertal monkey testis is heterogeneous with mitosis, being restricted to only a small fraction, the growth fraction as defined by Scholzen and Gerdes (14) cannot be excluded at the present time.

The finding that the mean number of Sertoli cells per testis in 1- to 2-d-old neonate and 4- to 5-month-old infant rhesus monkeys was 42 x 10⁶ and 156 x 10⁶, respectively, is consistent with our earlier study, which revealed that the number of this cell type in 7- to 18-d-old rhesus macaques was 57 x 10⁶ (4). In the latter study, the number of Sertoli cells in the testis of juvenile monkeys (15–17 months old) was also enumerated and found to be 286 x 10⁶. This represents an approximate 2-fold increase over that observed for the 4- to 5-month-old infants in the present study. Therefore, it would seem reasonable to propose that, in the monkey, Sertoli cells continue to proliferate throughout the juvenile phase of development; a notion that is strongly reinforced by the present finding that BrdU-labeled Sertoli cells were identified in the 14- to 17-month-old juvenile monkeys. Thus, the first of our proposed schemata to describe the postnatal pattern of Sertoli cell proliferation in higher primates (5) must be rejected because it posits that prepubertal proliferation of this somatic cell type is gonadotropin dependent and therefore is restricted to the first 6 months of postnatal life (infancy).

The second model, which posits that the increase in Sertoli cell number before puberty is gonadotropin independent and proceeds in a linear manner during this protracted phase of primate development, must also be rejected. Although there was a 4-fold increase in the mean number of Sertoli cells per testis during the 4- to 5-month period immediately after birth, the increase in Sertoli cell number during the subsequent 10–12 months of development was less striking (approximately 2-fold). The greater rate of increase in Sertoli cell number during infancy (birth to 4–5 months of age) compared with that for juvenile development (4–5 to 15–17 months of age) was entirely consistent with the finding that the Sertoli cell labeling index in neonates and infants was significantly greater than that in juveniles. In this regard, it is surprising to note that, in a recent study, Ki-67 labeling in testis collected from boys who died in hospital between 1 d and 5 yr of age as a result of multiple disease states, including, in the majority of cases, congenital cardiac malformations, failed to provide evidence for increased Sertoli cell proliferation during the first 6 months of life (15).

In view of the foregoing considerations, it seems reasonable to reject both of our original schemata and propose an alternative model, which is shown in Fig. 5. Here, although Sertoli cell proliferation continues during the relatively hypogonadotropic juvenile phase of primate development, amplification of the expanding population of Sertoli cells is greatest during infancy and puberty when secretion of gonadotropin is robust. The finding that premature stimulation of the juvenile monkey testis with FSH and LH elicits a precocious pubertal increase in Sertoli cell number (5) provides convincing evidence for a causal role of gonadotropin in this regard. That the elevated gonadotropin drive during infancy is also responsible for the heightened Sertoli cell proliferation at this stage of development, however, remains to be demonstrated empirically. In this regard, it may be noted that GnRH agonist-induced suppression of FSH and LH secretion during infancy in the rhesus monkey was associated with a pubertal delay in testicular growth (16), possibly reflecting impaired Sertoli cell proliferation during infancy.

View larger version (11K): [in this window] [in a new window]   FIG. 5. Schematic of Sertoli cell proliferation during postnatal development in the rhesus monkey. Note that the rate of increase in Sertoli cell number during infancy (extended broken line), a stage of development characterized by elevated circulating gonadotropin levels (shaded ghost), is greater than that during juvenile development. A second gonadotropin dependent burst in Sertoli cell proliferation occurs during puberty. Qualitatively, the model is applicable to the human situation. I, Infant; J, juvenile; P, pubertal; PP, postpubertal.

The foregoing schemata proposed for the postnatal proliferation of Sertoli cells in higher primates, however, does not appear to be applicable to New World monkeys. In the marmoset and cebus monkey, a pubertal increase in Sertoli cell number has not been observed, and the postnatal proliferation of Sertoli cells appears to be restricted to the neonate and infant phases of development (17, 18). Thus, although others (18) have argued that rodent and New World primate models of human Sertoli cell development are superior to those based on the rhesus monkey, this view now needs to be reevaluated.

Although circulating inhibin B levels were not measured in the present study, we have previously described the time course of this plasma hormone from birth to 1 yr of age in the male rhesus monkey (19). Interestingly, inhibin B concentrations increased from birth to reach peak values between 1 and 2 months of age before declining to plateau at the relatively low levels associated with the quiescent testis of the juvenile. Thus, it would seem that during this dynamic phase of prepubertal development, inhibin B secretion by the testis may reflect the rate of Sertoli cell proliferation, rather than the absolute number of this cell type.

In summary, we propose that Sertoli cell proliferation during postnatal development in the rhesus monkey and other higher primates, including man, occurs predominantly during infancy and puberty under the influence of elevated gonadotropin secretion that is observed at these stages of development. A schemata for this model of Sertoli cell proliferation in higher primates is shown in Fig. 5.

	Acknowledgments

 
The expert technical assistance of the staff of the Primate and Cell Imaging Cores of the Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, is gratefully acknowledged. We also thank June Marshall for preparing the line drawings.

	Footnotes

 
This work was supported by National Institute of Child Health and Human Development/National Institutes of Health through cooperative agreement (U54-HD-08610) as part of the Specialized Cooperative Centers Program in Reproduction Research.

A preliminary report of this work was presented at the Annual Meeting of the American Andrology Society, Seattle, WA, 2002 (Abstract 33).

Abbreviation: BrdU, 5-bromo-2'-deoxyuridine.

Received November 25, 2002.

Accepted June 14, 2003.

	References

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