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. 2006 Mar;208(3):373–379. doi: 10.1111/j.1469-7580.2006.00528.x

Effects of increased nerve growth factor plasma levels on the expression of TrkA and p75NTR in rat testicles

M B Levanti 1,*, A Germanà 1,*, F de Carlos 2, E Ciriaco 1, J A Vega 3,4, G Germanà 1
PMCID: PMC2100250  PMID: 16533319

Abstract

In addition to their well-known roles within the nervous system, the neurotrophins and their receptors regulate some functions in the reproductive system. In this study we used combined morphological and immunohistochemical techniques to investigate the presence and cellular localization in the rat testicle of the two receptors of nerve growth factor (NGF), i.e. TrkA and p75NTR. Furthermore, to evaluate whether increased plasma levels of NGF affect the ageing process, 4-methylcathechol (4-MC), an inductor of NGF synthesis, was administered. Both TrkA and p75NTR were expressed in rat testicles, but the pattern and intensity of immunoreaction were marginally different between them. In adult rats TrkA was expressed in spermatozoa and spermatids, and p75 was expressed in spermatogonia. In newborn rats TrkA immunoreactivity was found in the Leydig cells, whereas p75 was detected in a cellular layer that surrounds the seminiferous tubules. In adult treated animals the immunoreaction for TrkA and p75NTR was also localized in the spermatocytes, whereas in newborn treated rats no changes in the pattern of immunoreaction was observed. The present findings suggest a role of the NGF/TrkA/p75 system in the physiology of reproduction, but the practical relevance of this remains to be established.

Keywords: immunohistochemistry, neurotrophins, testicle, treated animals, Trk receptors

Introduction

In mammals, the family of the growth factors called neurotrophins (NTs) comprises four molecules, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and neurotrophins 4/5 (NT-4/5) (Barbacid, 1995), which are primarily involved in the development and maintenance of the nervous system (Fariñas, 1999). Nevertheless, the expression of NT receptors in non-neuronal tissues, and the effects of in vitro and in vivo experiments, strongly suggests that NTs have a broader range of actions than originally supposed. The functions of NTs outside the nervous system are still poorly known, but increasingly data suggest a role in the regulation of non-nervous tissues of these molecules (see Tessarollo, 1998; Vega et al. 2003), including the male and female reproductive system (Robinson et al. 2003; Levanti et al. 2005; Li et al. 2005; Moon et al. 2005).

NTs bind to two kinds of receptors with dissociation constants of 10−9 and 10−11 m, denominated low- and high-affinity receptors (Lewin & Barde, 1996). The low-affinity receptor is p75NTR, a protein belonging to the tumour necrosis factor receptor super-family, which serves as a pan-neurotrophin receptor mediating pro-apoptotic or pro-survival cell programs (Lu et al. 2005; Nykjaer et al. 2005). The protein tyrosine kinase Trk receptors TrkA, TrkB and TrkC act as specific high-affinity NT receptors (Lewin & Barde, 1996; Huang & Reichardt, 2001). TrkA is the preferred receptor for NGF, but has a lower affinity for NT-3 or NT-4/5 binding. TrkB is bound by BDNF and NT-4 and, to a lesser extent, by NT-3; TrkC has a unique ligand, NT-3 (for a review see Huang & Reichardt, 2003; Benito-Gutierrez et al. 2005).

NTs and their receptors promote development of the gonads (Levine et al. 2000; Dissen et al. 2002; Cupp et al. 2003) and regulate some functions in both the female (Abir et al. 2005; Kawamura et al. 2005) and the male (Muller et al. 1997) reproductive system. Regarding the testicle, they are involved in the progression of male sex determination, differentiation, induction of seminiferous cord formation and testicle morphogenesis (Russo et al. 1995, 1999; Cupp et al. 2000, 2003; Levine et al. 2000; Campagnolo et al. 2001; Park et al. 2001). NTs, especially NGF, TrkA and p75NTR, have consistently been detected in developing and adult testicles of different mammalian species (Russo et al. 1995; Seidl et al. 1996; Schultz et al. 2001; Li et al. 2005; Moon et al. 2005), and their expression has a hormonal regulation (Russo et al. 1999).

The endogenous synthesis of NGF and BDNF can be induced by administration of 4-methylcatechol (4-MC; Kaechi et al. 1993, 1995; Fukumitsu et al. 1999; Garcia-Suarez et al. 2000; Perez-Perez et al. 2003), which also stimulates phsophorylation of Trks and MAP kinases (Sometani et al. 2002). However, the immunohistochemical pattern of TrkA and p75NTR remains unchanged in the rat female genital tract after 4-MC treatment (M. B. Levanti et al., unpublished data). The aim of this study was to analyse whether increased levels of NGF induced by treatment with 4-MC has any effect on the expression of TrkA and p75NTR by adult rat testicle and therefore can act on testicular spermatogenesis.

Materials and methods

Treatment of rat tissues and blood samples

Male Wistar rats, aged 0 days (n = 16) and 3 months (n = 16), were used in this study. The testicles were removed under deep chloral hydrate anaesthesia (350 mg kg−1), collected and fixed in Bouin's fixative for 24 h, and routinely embedded in paraffin. Blood samples were collected from the tail artery in adults and directly from the heart in pups; they were placed in heparinized vials, centrifuged and the plasma was stored at −20 °C until use.

Induction of NGF synthesis

Pregnant female rats (n = 2) were treated daily for 21 consecutive days with 10 µg kg−1 b.w. 4-MC (Sigma, St Louis, MO, USA) in PBS (0.1 m, pH 7,4), and immediately after birth the pups (n = 11) were anaesthetized with ether, and the testicles were immediately removed; a blood sample form the heart was also obtained. Male Wistar rats (n = 10) aged 3 months were injected (i.p.) daily for ten consecutive days with 10 µg kg−1 4-MC, and 3 days after the last injection the animals were killed under chloral hydrate anaesthesia (350 mg kg−1). The testicles were removed and blood samples obtained. Two pregnant rats and ten adult males (3 months old) received a daily injection of the vehicle alone, during the same period of time; the two females, the pups (n = 10) and the adult males served as a control of the 4-MC-treated animals.

Measurement of plasma NGF levels

The measurement of NGF plasma levels in both control and 4-MC-treated animals were carried out by two-site ELISA as follows: 96-well plates were coated with a polyclonal anti-NGF antibody or with a rabbit pre-immune serum. After incubation for 12 h at room temperature, the wells were incubated for 2 h with blocking buffer (2% bovine serum albumin in 0.05 m bicarbonate buffer, pH 9.5). The wells were then washed repeatedly (0.05 m Tris/HCl buffer, pH 7.4, containing 200 mm NaOH, 5% gelatine and 0.15 Triton X-100) and incubated with the sera and the NGF standards for 12 h at room temperature. After rinsing, each well was incubated with 4 mU of anti-βNGF galactosidase (Boehringer Mannheim, Germany) for 2 h at 37 °C. The wells were washed again and incubated with 10 µL phenol red solution (mg mL−1) for another 2 h at 37 °C. Finally, the optical density at 575 nm measured using an ELISA and the standards was corrected by subtracting the control values, considered to represent the non-specific reaction. Statistical differences between experimental groups were evaluated by analysis of variance (anova). Values of P≤ 0.05 were considered as significant.

Single peroxidase immunohistochemistry

Tissue was cut into serial sections (10 µm thick), mounted on gelatine-coated microscope slides and processed for indirect peroxidase immunohistochemistry. To ascertain structural details, some representative sections were stained with haematoxylin–eosin.

Deparaffined and rehydrated sections were rinsed in Tris/HCl buffer (0.05 m, pH 7.5) containing 0.1% bovine serum albumin and 0.2% Triton-X 100. Endogenous peroxidase activity and non-specific binding were blocked (3% H2O2 and 25% fetal calf serum, respectively) and sections were incubated in a humid chamber overnight at 4 °C with rabbit polyclonal antibodies directed against p75NTR (diluted 1 : 100; Chemicon International Inc., Temecula, CA, USA; cat. no. AB1554) and TrkA (diluted 1 : 100; Santa Cruz Biotechnology, Santa Cruz, CA, USA; cat. no. sc-118). The antibody against TrkA maps within the tyrosine-kinase domain of human TrkA (763–777 residues). The antibody used to label p75NTR was directed against an extracellular fragment (residues 43–161) of mouse p75NTR. Thereafter, sections were washed and incubated for 90 min at room temperature with peroxidase-labelled sheep anti-rabbit IgG (Amersham, Bucks., UK), diluted 1 : 100. Sections were finally rinsed and the immunoreaction visualized using 3–3′ diaminobenzidine as a chromogen. The intensity of the immunostaining developed by each antibody was assessed directly under the microscope, by two independent researchers, and the results were expressed semi-quantitatively as strong (+++), high (++), faint (+) or non-reactive (–).

For control purposes, sections were processed in the same way but substituting the primary antibody by a non-immune rabbit serum, or omitting the primary or the secondary antibodies in the incubation (for p75 control); or incubating the sections with a specifically pre-absorbed TrkA antibody (50 µg mL−1 of the homologous antigen; peptide from Santa Cruz Biotechnology, cat. no. sc-118P). Moreover, to avoid cross-reactivity of TrkA antisera to other Trks, aliquots of each Trk antiserum were absorbed with an excessive amount of heterologous antigen (for details see Levanti et al. 2005). Under these conditions no specific immunostaining was detected.

Results

Expression of the two main receptors of NGF was investigated immunohistochemically in newborn and adult rat testicles. In the newborn animals, specific immunoreactivity (IR) for TrkA was detected in the Leydig cell islands localized among the seminiferous tubules in the interstitial parenchyma. In the walls of the seminiferous tubules, TrkA IR was observed in elongated cells scattered among the germinal cell layers of the seminiferous epithelium, identified as Sertoli cells on the basis of their morphology and distribution (Fig. 1a). This pattern was changed in adult animals. Indeed, TrkA IR was observed in all seminiferous tubules in elongated cells of the spermatic line placed at the luminal pole. The morphological features of the TrkA-positive cells as well as their distribution suggested that they corresponded to spermatids and spermatozoids (Fig. 1b). In addition, specific IR for TrkA was also found in cells organized in clusters around vessels throughout the whole testicles, identified as Leydig cells on the basis of their morphology and topographical localization (Fig. 1c).

Fig. 1.

Fig. 1

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Immunohistochemical detection of TrkA in the testicles of newborn (a), adult (b,c) and 4-methylcatechol-treated (d) rats. Specific TrkA immunostaining was mainly detected in the Leydig cells (asterisks), spermatids and spermatozoids, and the Sertoli cells. 4-Metylcatechol treatment results in an increased intensity of immunostainig and the presence of TrkA immunoreactivty in the spermatocytes, in addition to all the cell types of the untreated animals. Scale bars, 50 µm.

p75NTR IR was detected only in the cellular layer surrounding the seminiferous tubule of the newborn rats (Fig. 2a), whereas in the adult rats it was restricted to the basal layer of the seminiferous epithelium. These cells were round in shape and placed directly over the basal membrane, and were identified as spermatogonia (Fig. 2b).

Fig. 2.

Fig. 2

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Immunohistochemical localization of p75NTR in the testicle of newborn (a), adult (b) and 4-methylcatechol-treated (c) rats. In normal and treated newborn rats the immunoreactivity was localized only in the peritubular layer of the seminiferous tubule (c). Conversely, in adult normal rats immunostaining for p75NTR was found in spermatogonia (arrow in a), whereas after treatment it was also localized in spermatocytes (arrow in b). Scale bars, 50 µm.

Systemic administration of 4-MC in adult animals increased plasma levels of NGF in pregnant females and adult males by about 100% from 9.2 ± 3.2 and 0.9 ± 3.6 ng mL−1, respectively, to 19.8 ± 2.8 and 20.1 ± 2.8 ng mL−1, respectively, without significant differences between males and females. In pups, plasma levels of NGF were also elevated in comparison with controls, but the increase was lower, about 50% (from 8.01 ± 2.8 to 11.9 ± 2.8 ng mL−1). Injecting vehicle alone did not affect NGF plasma levels in any of the three groups of animals (Fig. 3). After the treatment, the structure and morphology of the testicle remained unchanged (data not shown). As a rule, the intensity of immunostaining for both TrkA and p75NTR was increased in treated animals, and cells displaying both proteins in newborn rats did not change with respect to the corresponding controls. In the adult rats the most noticeable changes were the occurrence of TrkA IR in spermatocytes, in addition to spermatogonia and spermatozoids (Fig. 1d), and of p75NTR in spermatocytes, which normally lack this protein (Fig. 2c).

Fig. 3.

Fig. 3

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Plasma levels of NGF in pregnant female (a), newborn males (b) and adult males (c), in normal conditions (N), after injection of the vehicle alone (V) and after treatment with 4-methylcatechol (4-MC) as described in the Materials and methods. Values are expressed in ng mL−1 and represent the mean ± SE of experiments carried out in triplicate. Significant differences (P < 0.05) between 4-MC-treated animals and the normal or vehicle-injected animals were found in all experimental groups.

The results are summarized in Tables 1 and 2.

Table 1.

Distribution of TrkA and p75NTR in the testicles of normal adult rats and after 4-methylcathechol treatment

Normal Treated
TrkA p75NTR TrkA p75NTR
Spermatogonia – + – +
Spermatocytes – – +++ +
Spermatids +++ – +++ –
Spermatozoids +++ – +++ –
Leydig cells ++ – ++ –
Sertoli cells – – – –
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The results are expressed semi-quantitatively as strong (+++), high (++), faint (+) or non-reactive (–).

Table 2.

Distribution of TrkA and p75NTR in the testicles of normal newborn rats and after 4-methylcathechol treatment

Normal Treated
TrkA p75NTR TrkA p75NTR
Germinal cells – – – –
Leydig cells +++ – +++ –
Peritubular layer – +++ – +++
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The results are expressed semi-quantitatively as strong (+++), high (++), faint (+) or non-reactive (–).

Discussion

In the last two decades evidence has accumulated for a role of NTs and their receptors in regulating the female and male reproductive system. All members of the NT family, as well as their signal-transducing receptors, have been localized in the testicle, suggesting that a paracrine or even autocrine mechanism might occur within this organ (Ojeda et al. 2000; Cupp et al. 2002; Robinson et al. 2003; Levanti et al. 2005; Li et al. 2005; Moon et al. 2005).

Here we investigated the cell localization of the NGF/p75/TrkA system in newborn and adult rat testicles, and whether a 4-MC-induced increase in NGF plasma level had any effect in the expression of these proteins, and therefore in the maturation of germ cells. The immunohistochemical analysis of rat testicles revealed the presence of p75NTR and TrkA, but with differences in the pattern of distribution. Previous data have demonstrated the occurrence of NTs and neurotrophin receptors in mouse, rat and human fetal testicles (Russo et al. 1999; Robinson et al. 2003; Li et al. 2005; Moon et al. 2005). In this study we have demonstrated the localization of TrkA in the Leydig cells of newborn rat testicles. Persson et al. (1990) detected NGF in germinal cells at all stages from primary spermatocytes to mature spermatozoids, as well as in the Leydig cells of rats. Given the presence of TrkA and p75NTR in the testicles, and the production of NGF within the organ, we hypothesize that an autocrine and/or paracrine loop occurs in the seminiferous tubules of rat testicle. By contrast, in both newborn and adult rat testicles, p75NTR was found in the peritubular layer and in spermatogonia. p75NTR has been previously detected in the interstitial compartment of embryonic mouse testicles, and during postnatal development it was also present in the myoid cell layer that surrounds the seminiferous tubules (Campagnolo et al. 2001). The same localization for p75NTR was observed in human fetal testicle (Robinson et al. 2003). Our findings, especially in newborn animals, match those results, and suggest that testicular maturation is accomplished by the absence of p75NTR.

The catechol derivative 4-MC is one of many substances known to induce NGF synthesis both in vitro and in vivo, up-regulating the basal levels of NGF mRNA expression (Carswell et al. 1992). It is not known either in what tissues 4-MC up-regulates NGF synthesis or the mechanism by which it does so, although it does not appear to be mediated by adrenergic receptors (Carswell et al. 1992). In our experiments, the 4-MC-treated animals showed an increase in NGF plasma levels of almost 100% in adult animals (males and females) as detected by two-site ELISA. By contrast, the increase was about 50% in pups born from 4-MC-treated mothers. Whether this is due to local synthesis of NGF in developing pups or is due to transfer of NGF from the mother to the placenta cannot be established. Nor did we investigate whether local induction of NGF synthesis in the testicle also took place. However, there were no major changes in TrkA and p75NTR expression in newborn treated animals, whereas in the adult animals 4-MC treatment induced occurrence of TrkA in spermatocytes, which is normally absent from this receptor. It has been suggested that in the adult testicle NGF is a potential regulator of meiosis in rat seminiferous epithelium (Russo et al. 1999), and the occurrence of TrkA in the spermatocytes of animals with increased plasma levels of NGF seems to support this. With regard to p75NTR, 4-MC induced the occurrence of this protein not only in spermatogonia but also in spermatocytes. Previous studies have demonstrated an organ-dependent regulation of p75NTR expression by NGF and 4-MC administration (Garcia-Suarez et al. 2000; Perez-Perez et al. 2003).

Taken together, our results suggest a possible involvement of TrkA and p75NTR and their ligands in the development and maintenance of the testicular seminiferous epithelium both during development and in adult life, and that increased levels of NGF could favour and improve spermatogenesis.

Acknowledgments

The present study was supported by a grant from the Italian M.I.U.R. (PRIN 2004) to G.G. We thank Mr Manuel Montero-Acosta for stylistic and critical reading of the manuscript. The technical assistance of Mr Vincenzo Sidoti is acknowledged.

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