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1 Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
2 Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
3 Ecological Effect Research Team, Dioxin and Environmental Endocrine Disrupter Research Project, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan
4 Toxicology and Effects Research Team, PM2.5/DEP Research Project, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan
(Requests for offprints should be addressed to A K Suzuki; Email: suzukiak{at}nies.go.jp)
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Abstract |
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Introduction |
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We recently isolated four nitrophenol derivatives –4-nitrophenol, 2-methyl-4-nitrophenol, 3-methyl-4-nitrophenol (PNMC) and 4-nitro-3-phenylphenol – from DEP and showed that they had vasodilatory activity (Mori et al. 2003, Taneda et al. 2004a), oestrogenic activity (Furuta et al. 2004, 2005, Taneda et al. 2004b), and anti-androgenic activity (Taneda et al. 2004b). In addition to its presence in DEP, PNMC is a degradation product of the insecticide fenitrothion (Bhushan et al. 2000), a widely used pesticide with high potential for human, livestock and poultry exposure in both rural and residential environments. The accumulation of PNMC from these sources could have significant effects on wildlife and human health via disruptions of endocrine and reproductive systems.
Despite the potentially significant effects, possible biological impacts and basic data on the toxicity of PNMC are still unknown. To determine the basic potential endocrine and reproductive toxicities of PNMC, we used the adult male terrestrial Japanese quail (Coturnix japonica). As a laboratory animal, Japanese quail has been extensively used in reproductive toxicity testing. Quail are considered to be representative of terrestrial birds and are accepted models for assessing both the acute and chronic effects of pesticides and other chemicals in wild birds (OECD 1993, EPA 1996), because spermatogenesis is well characterized (Lin & Jones 1992) and the cloacal gland is a good marker of gonadal development (Ottinger & Brinkley 1979a). In the present study, we used this animal model to examine the in vivo effects of a single dose of PNMC and the in vitro effects on the testicular function of adult male quail.
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Materials and Methods |
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PNMC (4-nitro-m-cresol) was purchased from Tokyo Kasei Kogyo Co. Ltd (Tokyo, Japan). Collagenase (type V), soybean trypsin inhibitor and Medium 199 (M199) were purchased from Sigma.
Birds
Japanese quail (Coturnix japonica) came from low antibody response (L) selected lines, in which chicks hatch after 17 days of incubation and the birds reach sexual maturity in 6 weeks. Birds were provided with food (Kanematsu quail diet; Kanematsu Agri-tech Co. Ltd, Ibaraki, Japan) and water, and were allowed to feed ad libitum. Male birds (6–9 weeks old) were housed in metal cages in a controlled environment (lights on, 0500–1900 h; temperature, 23 ± 2 °C; humidity, 50 ± 10%; air exchanged 20 times hourly). This study was conducted in accordance with the Guiding Principles in the Use of Animals in Toxicology, and was approved by the Animal Care and Use Committee of the Japanese National Institute for Environmental Studies.
Administration of PNMC
Mature male Japanese quail were treated with a single i.m. injection of PNMC (78, 103 or 135 mg/kg body weight). The doses were decided by the preliminary experiments on half-maximal lethal dose (LD50) of PNMC in the adult male quail. The LD50 of PNMC in the adult male quail was 135 mg/kg, so the three lower doses (including 135 mg/kg) were adopted in this study. Controls were injected with vehicle alone (PBS containing 0.05% Tween 80). The quail (n=6–9 per group) were weighed and killed by decapitation at 1, 2 and 4 weeks after the injection. Following decapitation, blood samples were collected in heparinized plastic tubes and centrifuged at 1700 g for 15 min at 4 °C. Plasma was separated and stored at –20 °C until it was assayed for testosterone and luteinizing hormone (LH). The testes were collected and weighed, and the cloacal gland area (longest length x greatest width) was measured.
Regrouping according to testicular atrophy
Birds with testicular atrophy were found in all PNMC-treated groups, but none was found in the control groups. Birds were separated into three atrophy groups (severe, intermediate and mild) on the basis of testicular weight. The severe atrophy group included birds in which the weight of both testes was at least 50% (1.33 ± 0.064 g) lighter than the mean of the control group (2.66 ± 0.128 g). The intermediate group included birds with one testis weighing less than 50% of the control weight. The criterion for the mild atrophy group was one testis weight of 50–70% of the control weight.
Histopathology
After weighing, the testes were immediately fixed in 4% paraformaldehyde (Wako Japan Co, Osaka, Japan) in 0.05 M PBS (pH 7.4), and embedded in paraffin. The paraffin-embedded testes were serially sectioned at 6 µm and placed on poly-L-lysine-coated slides (Sigma) for haematoxylin and eosin staining, and examined by light microscopy for histology.
Effects of PNMC on hypothalamus–pituitary function
To observe the direct effects of PNMC on the secretion of LH, birds were treated with a single i.m. injection of a small amount of PNMC (25 mg/kg) to avoid the acute toxic effect that was observed at the highest dose setting (see Results). Control birds were treated with vehicle alone (PBS containing 0.05% Tween 80). Eight birds were used in both groups. Blood was collected in heparinized syringes from the jugular vein 1 and 3 h after the injection. Six hours after the injection, birds were killed by decapitation and blood was collected. All blood samples were centrifuged at 1700 g for 15 min at 4 °C, and plasma was separated and stored at –20 °C until it was assayed for LH.
Interstitial cell preparation
Interstitial cell preparations containing Leydig cells were prepared from the testes of adult quail as described previously (Klinefelter et al. 1987) with minor modifications. Adult quail were killed by cervical dislocation and the testes immediately removed. Testicular cells were dispersed by treating the decapsulated testis in M199 with 0.71 mg/ml sodium bicarbonate and 2.21 mg/ml HEPES containing collagenase (0.25 mg/ml) and soybean trypsin inhibitor (0.025 mg/ml) at 37 °C for 30 min in a shaking water bath. After incubation, the supernatant, containing Leydig cells, was decanted through nylon mesh to remove debris. The cells were washed by centrifugation and resuspended in 10 ml M199 with 1% fetal bovine serum. The viability of the cells was evaluated by means of the trypan blue exclusion test and was found to be 92%. Cells (105 cells/well per 100 µl) were cultured in 96- well culture plates at 37 °C under a 95% air–5% CO2 atmosphere. Following a 20 min equilibration period, cells were exposed for 4, 8 or 24 h to 10–6, 10–5 or 10–4 M PNMC (100 µl) dissolved in M199. The viability of treated cells was determined by a lactate dehydrogenase (LDH) Cytotoxicity Detection Kit (code number MK401; Takara, Japan). No significant differences in LDH release activity were observed between cells treated with PNMC and control cells (data not shown). Conditioned media were assayed for testosterone.
Determination of LH and testosterone concentrations in plasma, and of testosterone concentrations in conditioned media
Plasma concentrations of LH and testosterone, and testosterone concentrations in conditioned media, were determined by specific RIAs. LH concentrations were measured with a USDA-ARS RIA kit (Beltsville, MD, USA) for chicken LH. The antiserum used was anti-avian LH (HAC-CH27–01 RBP75). The hormone for iodination was chicken USDA-cLH-I-3. The results are expressed in terms of USDA-cLH-K-3. The intra- and inter-assay coefficients of variation were 5.2 and 11.2% respectively. USDA-cLH-I-3 and USDA-cLH-K-3 were kindly provided by Dr John A Proudman, Biotechnology and Germplasm Laboratory, Animal and Natural Resources Institute, Beltsville, MD, USA (Krishnan et al. 1994). The antiserum against avian LH was kindly provided by the Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma, Japan (Hattori & Wakabayashi 1979).
Plasma concentrations of testosterone were determined by a double-antibody RIA system with 125I-labelled radioligands as described previously (Taya et al. 1985). The antiserum against testosterone (GDN 250) (Gay & Kerlan 1978) was kindly provided by Dr G D Niswender, Colorado State University (Fort Collins, CO, USA). The intra- and inter-assay coefficients of variation were 6.3 and 7.2% respectively.
Statistical analysis
All data are expressed as means ± S.E.M. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test. The acute effects of PNMC on the secretion of LH challenges were analyzed using two-way ANOVA followed by Dunnett’s test. Statistical analysis was performed using the software program StatView 5.0 (SAS Institute Inc, USA). A probability value of P < 0.05 was considered significant.
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Results |
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Of 28 birds treated with the highest dose of PNMC (135 mg/kg), 6 died within 10 min of treatment (Table 1
). Of 26 birds in the 103 mg/kg treatment group, one bird died. The birds showed behaviour such as dyspnoea, opening the beak and tremor prior to death. No birds died in the 78 mg/kg or control groups. The surviving birds in all treatment groups grew normally, with no differences in body weights (data not shown).
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Results for testicular atrophy are shown in Tables 1
and 2. The morphology and histology of atrophic testes are shown in Fig. 1. PNMC treatment induced testicular atrophy as early as 1 week after treatment, but neither the severity nor the incidence of atrophy showed a dose-dependent relationship (Table 1). The highest rate of testicular atrophy was observed 2 weeks after treatment with PNMC in all groups. In birds receiving 78 and 103 mg/kg PNMC, 70 and 67% of birds showed testicular atrophy respectively (Table 1). Some birds showed significant weight decreases in both testes, but others showed an asymmetrical decrease (Table 2). In most cases, the right testis was significantly decreased in size, whereas the left testis was not significantly different from the controls (Table 2).
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Overall testicular morphology was normal in the control group (Fig. 1A), whereas PNMC treatment induced severe atrophy, either bilaterally or on the right side only (Fig. 1B and C). Control sections showed compartmentalization of germ cells in the seminiferous tubules, with spermatozoa visible in normal-sized lumen (Fig. 1D). In birds with testicular atrophy on one side, seminiferous tubules contained only a thin layer of spermatogenic lineage cells, and spermatids and spermatozoa were absent (Fig. 1E). In contrast, paired atrophic testes showed no compartmentalization of germ cells or spermatozoa, and had highly atrophic seminiferous tubules that were devoid of all cells except spermatogonia and Sertoli cells (Fig. 1F). Control cloacal glands had normal morphology and produced cloacal gland foam (Fig. 1G), whereas PNMC-treated birds with testicular atrophy had smaller cloacal glands and did not produce cloacal foam (Fig. 1H and I).
Plasma concentrations of LH and testosterone
Plasma concentrations of LH and testosterone in PNMC-treated birds are shown in Figs 2 and 3. There were no treatment-induced changes in basal levels of plasma LH at any time point, with relatively large individual variation (Fig. 2). Plasma concentrations of testosterone were significantly lower in both the 78 and 103 mg/kg-treated groups at 1, 2 and 4 weeks after PNMC treatment (Fig. 3A and B), whereas the high-dose group showed a significant decrease only at 4 weeks after treatment (Fig. 3C).
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. There are two types of circulating levels of LH in PNMC-treated birds having various grades of atrophy of the testes. The first type of bird revealed that plasma concentrations of LH were significantly lower in the severe atrophy group (1.34 ± 0.45 ng/ml) as compared with controls (4.66 ± 0.61 ng/ml) (Table 2). Plasma concentrations of LH in this type of bird decreased with increasing severity of testicular atrophy, and the level correlated with testis weight. In this type of bird, plasma concentrations of testosterone were significantly lower in severe, intermediate and mild atrophy groups as compared with controls. It is also correlated with testis weight (Table 2). On the other hand, the second type of bird showed plasma concentrations of LH that were higher compared with controls although they had atrophic testes and low levels of testosterone. This type of bird was observed in 1 out of 6, 2 out of 6, and 4 out of 16 of the birds in the severe, intermediate and mild atrophy groups respectively. Data are shown in parentheses in each group (Table 2). Cloacal gland area
Cloacal gland area was significantly decreased in all atrophy groups, with the lowest value observed in the severe atrophy group. Changes in cloacal gland area were similar to plasma levels of testosterone (Table 2).
Acute effects of PNMC on secretion of LH
There was a clear time-dependent decline in plasma LH concentrations in the group treated with PNMC (Fig. 4). PNMC treatment (25 mg/kg) significantly reduced plasma LH concentrations (P < 0.05) from 1 h after injection.
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The dose- and time-dependent effects of PNMC on testosterone secretion into interstitial cell cultured medium were examined (Fig. 5). In the cells exposed to PNMC for 4 h, the amount of testosterone secretion was almost the same as in the control groups. However, a significant reduction in testosterone secretion was detected in cells treated with 10–6, 10–5 or 10–4 M PNMC for 8 h, and in cells treated with 10–6 and 10–5 M PNMC for 24 h.
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Discussion |
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The acute toxicological responses were observed from the birds treated with the high dose (135 mg/kg), and the conditions encountered were dyspnoea and tremor prior to death. From these conditions it can be speculated that PNMC causes acute toxicity and death, possibly by a blood pressure drop followed by an ischaemic shock, as it has been reported that PNMC has a potent vasodilating activity (Mori et al. 2003, Taneda et al. 2004a).
The present study clearly demonstrated that there are two types of responses in secretion of LH and testosterone in PNMC-treated birds. In the first type, PNMC-treated birds showed low plasma levels of both LH and testosterone. On the other hand, the second type of bird treated with PNMC showed high levels of LH but low levels of testosterone. These results clearly indicate the site of action of PNMC in male quail. The first type of response suggests a direct effect of PNMC on the hypothalamus and pituitary axis to reduce secretion of LH. In this case, therefore, it is suggested that PNMC firstly act on the hypothalamus to reduce pulsatile secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamus, and then reduces pulsatile secretion of LH from anterior pituitary glands, followed by a reduction of testosterone secretion from the testis. In addition, in the present study, we demonstrated that plasma concentrations of LH were significantly decreased from 1 h after a single injection of PNMC. These results strongly support the supposition that PNMC may act directly on the hypothalamus–pituitary axis to reduce GnRH release from the hypothalamus, and subsequently reduce LH release from the anterior pituitary gland. On the other hand, the second type of response suggests a direct effect of PNMC on the testis to reduce secretion of testosterone. In this case, it is suggested that PNMC firstly acts directly on the testes to reduce testosterone secretion. This reduction of testosterone induces hypersecretion of GnRH from the hypothalamus and subsequently increased secretion of LH from anterior pituitary glands. It is well known that Leydig cells play a crucial role in synthesizing testosterone and regulating the process of spermatogenesis (Senger 1999). Alteration of Leydig cell function can lead to adverse effects on testicular functions (Senger 1999). In the present study, we have demonstrated that PNMC reduces testosterone production in cultured testicular interstitial cells. This observation is in agreement with in vivo studies of the second type of bird that showed higher LH levels and lower testosterone levels, in which the testosterone levels were suppressed prior to the toxic effects to the pituitary that would reduce the LH levels. The present results, therefore, strongly suggest that PNMC has a direct effect on the testis, in addition to the hypothalamus and the pituitary; however, an exact explanation of these two different types of response is not possible at the present time.
Testicular atrophy often showed an asymmetric response, with atrophy most frequently observed in the right testis. A characteristic feature of sexual development in both female and male birds is gonadal asymmetry: the right ovary does not develop, and the right testis is often slightly smaller than the left (Lillie 1952). Treatment of avian embryos with an oestrogenic chemical, diethylstilboestrol, induces a similar asymmetrical pattern, with greater atrophy in the right testis (Rissman et al. 1984, Perrin et al. 1995). In birds, the left embryonic gonad has ambisexual potential, whereas the right gonad is exclusively masculine (Perrin et al. 1995). The mechanism underlying this phenomenon requires further study.
The atrophic paired testes showed no compartmentalization of germ cells and spermatozoa, and seminiferous tubules were atrophic and almost devoid of cells except for the spermatogonia and Sertoli cells. These results suggest that circulating gonadal hormones in the treated birds were reduced with the addition of the toxic effects of PNMC to the seminiferous tubules. The direct effect of PNMC on testes results in a decrease in spermatogenesis, leading to a reduction in the sperm production of treated birds. In avian testes, interstitial cells (Leydig cells), as well as testicular germ cells and Sertoli cells, contain steroidogenic enzymes, which produce progesterone, androgen and oestrogen (Purohit et al. 1977, Kwan et al. 1995, Rosenstrauch et al. 1998). Thus, steroidogenic activities were destroyed in the treated-group testes because the seminiferous epithelium was thinner and thus decreased the sperm population.
The present study showed that the cloacal gland area in birds with testicular atrophy was significantly smaller than that in normal birds. The androgen-dependent cloacal gland, posterior to the cloaca, is a secondary sex characteristic unique to the genus Coturnix. The cloacal gland contains androgen receptors and grows in response to circulating androgen (Ottinger & Brinkley 1979a, 1979b, Balthazart et al. 1984, Kaku et al. 1993), so it is a widely used indicator of androgen status in the male during sexual maturation. The decrease in cloacal gland area in the treated groups may be attributed to the reduced testosterone level recorded in the present study.
We have reported earlier that PNMC isolated nitro-phenol derivative compound from DEP has been shown to posses oestrogenic activity in vivo and in vitro (Taneda et al. 2004b, Furuta et al. 2004, 2005). A previous paper reported that an oestrogenic chemical bisphenol-A reduced the weight of the combs and testes in the male chicken (Furuya et al. 2003). It is well known that the growth of the comb and testes are highly promoted by testosterone and inhibited by oestrogen (Balthazart & Hendrick 1978). In addition, PNMC also has anti-androgenic activity in vitro (Taneda et al. 2004b). Previous reports have shown that flutamide, a potent androgen antagonist, decreased accessory sex organ weight in rats in vivo (Yamada et al. 2000, Ashby et al. 2004). It is suggested that the oestrogenic and anti-androgenic potency of PNMC may be involved in the suppression of testicular function in the PNMC-treated quail in the present study. In the present study, the effect of PNMC on the secretion of testosterone is not dose dependent. However, the present results suggest that the ratio of oestrogenic and anti-androgenic potency of PNMC may be involved in this phenomenon.
The present study is also important from an environmental perspective. A remarkable amount of DEP are discharged into the air of many countries. In Japan 58 902 tons (Japan Environmental Agency 1998) are emitted each year; an amount that can not be ignored. The amount of PNMC that is included in 1 kg of DEP is 28 mg (Taneda et al. 2004a). The environmental concentrations of PNMC are not well known since research into the isolation of the compounds found in DEP has only just begun. In addition, PNMC is a known degradation product of the insecticide fenitrothion (Bhushan et al. 2000), which is used widely in many countries and is accumulating in air, soils and water (Nishioka et al. 1988, Nishioka & Lewtas 1992). According to the data submitted by the pollutant release and transfer registers (PRTR), the amount of fenitrothion emitted into the environment in 2002 in Japan was approximately 1300 tons, and roughly half of this is degraded into PNMC (Hayatsu et al. 2000). Asman et al.(2005) also reported that the amount of PNMC contained in the rainwater in Roskilde, Denmark was as high as 2483 ng/l. These findings clearly indicate that PNMC exists in large amounts in the environment from diesel exhaust, fenitrothion used on farms, and in rain-water. It is difficult to directly interpret the present results of the effects of PNMC on wildlife since the doses do not relate to the environmental concentration. However, as seen in the results from this research, it is certain that PNMC has toxic effects on the reproductive system, and therefore the possibility that the large amounts of PNMC in the environment will have serious effects on wildlife and human beings can not be ignored.
In conclusion, the present study clearly shows that PNMC impairs reproductive function in male Japanese quail through toxic effects on the hypothalamus, pituitary and testis.
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Acknowledgements |
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References |
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Received in final form 17 February 2006
Accepted 22 February 2006
Made available online as an Accepted Preprint 24 February 2006
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) or PNMC (25 mg/kg; •). Each bar represents the mean ± S.E.M. of eight quails per group. *P < 0.05 compared with control when analyzed using two-way ANOVA followed by Dunnett’s test.