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From the Departments of * Anatomy II and
Pharmacology, Azabu University School of
Veterinary Medicine, Sagamihara, Japan.
| Correspondence to: Dr Masako Yamamoto, Department of Anatomy II, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 229-8501, Japan (e-mail: masako{at}azabu-u.ac.jp). |
| Received for publication July 2, 2004; accepted for publication November 5, 2004. |
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Abstract |
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mitochondrial RNAs (mRNAs) were unchanged, although
the StAR (steroidogenic acute regulatory protein) mRNA expression level was
increased at 6 weeks. On the other hand, when PCB169 was administered, plasma
testosterone levels were decreased at 3 and 6 weeks and were increased at 15
weeks. Plasma luteinizing hormone (LH) levels were decreased at 6 weeks, and
plasma follicle-stimulating hormone (FSH) levels were increased at 15 weeks.
The expression levels of 3ß-HSD and P45017 were
increased, and the mRNA level of 5-reductase 1 was decreased at 15
weeks. PCB169 treatment suppressed the conversion of round spermatids between
stages VII and VIII. These results indicate that in utero and lactational
exposure to PCB126 or PCB169 decreases plasma testosterone levels in
3-week-old rats, with no change in the expression levels of the mRNAs of
enzymes, and that PCB169 inhibits testicular steroid synthesis more strongly
than PCB126. PCB169 greatly altered the concentration of testosterone,
indicating a stronger inhibitory effect on spermatogenesis. Low testosterone
and LH levels in prenatally PCB169-exposed rats until 6 weeks after birth
presumably retard the functional differentiation of testicular Leydig cells;
however, the increased testosterone levels at 15 weeks suggest that Leydig
cells in PCB-exposed rats are virtually mature by the 15th week.
Key words: PCB, androgen, pituitary
The toxicity of these homologs is evaluated by the toxicity equivalence factor (TEF), which is the relative toxicity when that of the most toxic TCDD is defined as 1; for example, 3,3',4,4',5-pentachlorobiphenyl (PCB126) has a TEF of .1, and 3,3',4,4',5,5'-hexachlorobiphenyl (PCB169) has one of .01 (Van den Berg et al, 1998). Many studies have investigated the inhibitory effects of PCBs on reproductive function, developmental abnormality, and impaired reproductive ability (Sager, 1983; Brezner et al, 1984; Sager et al, 1987, 1991; Safe, 1990; Backlin and Bergman, 1992; Hansen, 1998). Also, several studies have reported the effects of PCBs on the in vivo and in vitro synthesis of steroids in the testis and adrenal gland or on spermatogenesis (Goldman and Yawetz, 1992; Kovacevic et al, 1995; Pflieger-Bruss et al, 1999). Data available for individual PCB congeners are from reproductive studies in laboratory animals with commercial PCB mixtures. Furthermore, few experiments with single PCBs administered exclusively during the prenatal period have been performed, and the precise mechanisms of PCB-induced abnormalities in the testicular steroid-synthesizing system and spermatogenesis have not been elucidated.
In this study, we aimed to elucidate the mechanism of the influence of PCBs on spermatogenesis and steroidogenesis in the male immature and mature offspring of mothers that had received PCBs of different structures, PCB126 and PCB169, during pregnancy.
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Materials and Methods |
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After birth, the pups were controlled to 4 males and 4 females in each litter. The pups were kept with their natural mothers until weaning on day 21. Male rats at postnatal weeks 3, 6, and 15 were autopsied under diethyl ether anesthesia to collect blood samples individually. The testes of each pup were removed, and the left testis was subjected to RNA extraction and the right testis to histologic analysis.
To determine the transplacental transfer of PCBs, at 20 days of gestation, 3 dams of each group were autopsied. Eight fetal livers in each litter were pooled and stored at -80°C.
The study described in this paper was carried out in accordance with the Azabu University Animal Experiment Guidelines.
PCB Analysis
Metocean Environment Inc (Tokyo, Japan) analyzed the pooled fetal livers
for content of PCB126 or PCB169 by high-resolution gas chromatograph-mass
spectrometry.
Plasma Hormone Assay
The blood samples were centrifuged at 4°C, and the plasma was stored at
-80°C until assay. The concentration of plasma testosterone was measured
by radioimmunoassay with the [125I] total testosterone assay kit
(Diagnostic Products Corp, Los Angeles, Calif). The sensitivity was determined
to be 4 ng/dL. The concentrations of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) were measured by the rat luteinizing
hormone enzyme immunoassay system and the rat FSH [125I] Biotrak
assay system (Amersham Biosciences, Buckinghamshire, United Kingdom). The
sensitivities were determined to be 0.1 ng/mL and 0.9 ng/mL, respectively.
Morphological Analysis of Leydig Cells
At autopsy, testes at 3 weeks were immediately frozen in embedding OCT
compound (Sakura Finetechnical Co Ltd, Tokyo, Japan) with liquid nitrogen.
Frozen sections (8 µm) were air dried for a few minutes, fixed in acetone
at -20°C for 10 minutes, and completely air dried. Five slides for each
sample were stained by tetrazorium reactions
(Levy et al, 1959) to detect
3ß-hydroxysteroid dehydrogenase (HSD). Stained sections were digitized by
a Nikon Coolpix 990 digital camera (Nikon Co, Tokyo, Japan) attached to a
light microscope, and the images were input into Adobe Photoshop 5.5 image
editing software (Adobe, San Jose, Calif). The area of the
3ß-HSD-positive cells and the whole area of the testis was measured with
NIH Image (National Institutes of Health, Bethesda, Md). The area ratio was
expressed as a percentage and averaged across the sections observed in each
testis.
Spermatogenesis
Testes at 6 and 15 weeks were fixed with Boiuns fluid. Fixed testes were
dehydrated, embedded in paraffin, and sectioned at 5 µm. Sections were
stained with periodic acid-Schiff and counterstained with hematoxylin.
Seminiferous tubules were staged according to the criteria published by Hess
(1990). Five hundred tubules
per testis were classified into the following groups: stage I, II/III, IV, V,
VI, VII, VIII, IX, X, XI, XII, XIII, and XIV.
Semiquantitative Reverse Transcription-PCR
Total RNA from the testis of offspring from intact and PCB-treated mothers
was extracted with Isogen (Nippon Gene Co, Toyama, Japan) according to the
manufacturer's protocol.
PCR amplification from reverse-transcribed complementary DNA (cDNA) was
carried out with the following primers: StAR (steroidogenic acute regulatory
protein), P450scc, 3ß-HSD, P45017
(17-hydroxylase + C17-21 lyase), 5-reductase 1, and
ß-actin (Table 1). The
reactions were performed according to the manufacturer's instruction for the
SuperScript 1-step reverse transcription (RT)-PCR (Invitrogen). Total volume
of 50 µL of the reaction mixture contained RNA, 10 nM sense and antisense
primers, tag Mix and 1x reaction mix, or 2.0 mM MgSO4 for
3ß-HSD. cDNA synthesis and predenaturation were performed with 1 cycle of
50°C for 30 minutes and 94°C for 2 minutes. Amplification was carried
out in a thermal cycler (Bio-Rad), as shown in
Table 2.
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Following PCR, the amplified DNA was separated by electrophoresis in a 2.5% agarose gel with an appropriate molecular mass marker (Bio-Rad, Hercules, Calif). Gels were stained with ethidium bromide and photographed with a Polaroid camera, and the intensity of the band was digitized on an Epson scanner. The signal intensities were measured in 3 individual animals and 2 independent RT-PCRs for each sample. The digitized signals were imported into NIH Image, and the average optical density of each band was measured and normalized to ß-actin to obtain the ratio of target product to ß-actin for each sample.
Statistical Analysis
Duncan's new multiple range test was used for statistical analysis of
results, with significance at P less than .05.
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Results |
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Hormone Levels
The plasma testosterone levels in the offspring of both PCB-administered
groups were significantly lower than those in the offspring from the control
group at 3 weeks after birth (Table
4). At 6 weeks after birth, the plasma testosterone levels in the
offspring from the PCB169-administered group were significantly lower than in
the offspring from the control group, but those in the offspring from the
PCB126-administered group were unchanged. At 15 weeks after birth, plasma
testosterone levels in the offspring from the PCB169-administered group were
significantly increased compared with those in the control offspring.
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At 3 weeks after birth, the plasma LH levels in the offspring from the PCB-administered groups did not significantly differ from those in the control offspring. At 6 weeks after birth, the plasma LH levels in the offspring from the PCB169-administered group were significantly lower than in the control offspring.
At 6 weeks after birth, the plasma FSH levels in the offspring from the PCB-administered groups did not significantly differ from those in the control offspring. At 15 weeks after birth, the plasma FSH levels in the offspring from the PCB169-administered group were significantly higher than those in the control offspring.
Leydig Cells and Spermatogenesis
In the testis interstitium of the 3-week-old offspring from the control
group, there were few Leydig cells, with small cytoplasm and a large number of
mesenchymal cells. At 3 weeks after birth, the ratios of the area of
3ß-HSD-positive cells to the whole area of the testis in the offspring
from the PCB-administered groups were lower than those in the control
offspring (Table 5).
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At 6 weeks after birth, matured spermatids did not yet present in the lumen of the seminiferous tubules from all groups (Figure 1). However, the stages of the cycle in testicular seminiferous epithelium could be divided into 13 stages, and the obtained frequency of the stages in the control group was almost equal to the result of the previous study (Hess et al, 1990). The number of stage VI seminiferous tubules was significantly higher in the offspring from the PCB-administered groups than in the offspring from the control group (Table 6). The administration of PCB126 reduced the number of stage XIII seminiferous tubules, whereas the administration of PCB169 reduced the numbers of stage II/III, VII, and IX seminiferous tubules. At 15 weeks after birth, the number of stage XI seminiferous tubules was significantly higher in the offspring from the PCB-administered groups than in the offspring from the control group. The administration of PCB126 reduced the number of stage XII seminiferous tubules, whereas the administration of PCB169 reduced the numbers of stage I, V, and VI seminiferous tubules and increased the numbers of stage II/III and VII seminiferous tubules. Pathologic changes, such as pyknotic nuclei and the occurrence of cell debris, were not detected in the testis from PCB-treated groups at 6 and 15 weeks (Figure 1).
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Expression Levels of StAR, Steroidogenic Enzymes (P450scc, 3ß-HSD, P45017), and 5-Reductase 1 Mitochondrial RNAs
The expression levels of StAR, P450scc, 3ß-HSD,
P45017, and 5-reductase 1 mitochondrial RNAs (mRNAs)
were semiquantitatively analyzed by RT-PCR
(Figure 2). The expression
levels of StAR did not change in the 3- and 15-week-old offspring from the
PCB-administered groups but were significantly higher in the 6-week-old
offspring from the PCB126-administered group than in the PCB169-administered
group. The expression levels of P450scc mRNA in the testis did not change in
all experimental periods. The expression levels of 3ß-HSD mRNA in the
testis did not change in the 3- and 6-week-old offspring from the
PCB-administered groups, but were significantly higher in the 15-week-old
offspring from the PCB-administered groups than in the control offspring. The
expression levels of P45017 mRNA were also unaffected by PCB
administration in the 3- and 6-week-old offspring but were significantly
increased in the 15-week-old offspring from the PCB169-administered group. The
levels of 5-reductase 1 mRNA expression were significantly higher in
the 6-week-old offspring from the PCB126-administered group, significantly
lower in the 15-week-old offspring from the PCB126-administered group, and
still lower in the 15-week-old offspring from the PCB169-administered group
compared with those in the control offspring.
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Discussion |
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This experiment produced a new finding, showing that the administration of PCB169 to pregnant rats tended to decrease plasma testosterone levels in their offspring up to 6 weeks after birth but significantly increased the levels in the 15-week-old offspring. We demonstrated that maternally administered PCB126 or PCB169 passed through the placenta in absolute form. Although, PCB126 was detected in fetal livers from the PCB169-administered group, the purity of administered PCB126 was approximately 99%, so PCB126 might have contained PCB169. Because the amounts of PCB126 found in PCB169 were approximately 5% in terms of TEF, these amounts might have resulted in an unconsidered effect on the PCB169-induced changes in this study. The highly chlorinated (14C) PCBs (Aroclor 1260) that accumulated in the maternal rats transferred to the fetuses and sucklings, and the PCB concentration in the milk increased gradually for 16 days after delivery and then decreased (Takagi et al, 1986). In this study, the administered PCBs were transferred to the fetuses during pregnancy and were transported to the offspring postnatally via milk; therefore, mother-derived PCBs decreased the plasma testosterone levels in the 3- and 6-week-old offspring. It appears that PCB169 influences testosterone levels more strongly than PCB126. The highly chlorinated congeners had a longer retention time in rat tissues (Shain et al, 1986). Because the dose of PCB169 was determined such that it was equal to the toxicity equivalence factor of PCB126, the higher inhibitory effect of PCB169 on testicular function might be a result of its structure.
Testosterone is the predominant androgen involved in the regulation of normal spermatogenesis in the rat because of its high intratesticular concentration (Wright and Frankel, 1979). It is known to preferentially induce the conversion of round spermatids between stages VII and VIII (O'Donnel et al, 1994, 1996). The content of androgen receptors (AR) is maximal in Sertoli cells at stages VII and VIII (Shan et al, 1997). We speculate that the increase in the number of stage VI seminiferous tubules and the decrease in stage VII seminiferous tubules in the 6-week-old offspring from the PCB169-administered group were because of the decrease in the concentration of plasma testosterone, resulting in the inhibition of the conversion of round spermatids between stages VII and VIII. Conversely, the concentration of plasma testosterone in the 15-week-old offspring from the PCB169-administered group was increased, but the ratio of the number of stage VIII seminiferous tubules to that of stage VII seminiferous tubules, which indicates an accelerated conversion of round spermatids, remained unchanged. However, the decreases in stage V and VI seminiferous tubules could be proof that the development of stage VII round spermatids was promoted. Meachem et al (1998) concluded that FSH acts on stages XIV through I (type A3 and A4 spermatogonia) of spermatogenesis on the basis of the number of FSH receptors (Kangasniemi et al, 1990) and the level of FSH receptor mRNA expression (Heckert and Griswold, 1991). Therefore, we speculate that the decrease in the number of stage I seminiferous tubules and the increases in those of stage II and III in the 15-week-old offspring from the PCB169-administered group were caused by an increase in the concentration of FSH, resulting in the stimulation of stage XIV and I spermatogonia, thereby promoting the progression from stage I to stages II and III.
It is still a matter of controversy whether maternal exposure to TCDD affects spermatogenesis in offspring. Mably et al (1992c) reported that perinatal exposure to a low TCDD dose significantly reduced testis weight and daily sperm production, whereas Gray et al (1997) and Ohsako et al (2001) failed to find this. On the other hand, Faqi et al (1998a) found a slight decrease of daily sperm production with no changes in testicular weight by administering female rats an initial loading dose 2 weeks before mating, followed by a weekly maintenance dose. Furthermore, there were no reports that maternal exposure to the PCB congeners altered the steroidogenesis or spermatogenesis of male offspring, especially an increase in plasma testosterone concentrations in male offspring after puberty, born to TCDD- or PCB congeners-exposed dams, although lactational exposure to Archor 1242 increased daily sperm production and testicular weight (Kim, 2001). We showed for the first time that maternal exposure to PCB169 affects steroidogenesis, resulting to alterations of the spermatogenesis in male offspring.
Desaulniers et al (1999) speculated that PCB126 administration inhibits LH release from the pituitary gland and damages the hypothalamus because they found that the twice-daily administration of high doses (100 or 400 µg/kg/d) of PCB126 to adult male rats reduced plasma LH levels and increased LH levels in the pituitary gland. However, a single dose of TCDD on GD 15 to pregnant rats did not change the plasma LH concentrations in male offspring (Mably et al, 1992c). In this study, although testosterone levels were decreased in the 3-week-old offspring from PCB126-administered dams and in the 3- and 6-week-old offspring from PCB169-administered dams, LH levels were unchanged or decreased. Therefore, we consider that maternally administered PCBs exert inhibitory effects on the interrelationship of the hypothalamus-pituitary-testis system in the offspring.
We investigated whether PCBs exert direct inhibitory effects on the testosterone-synthesizing ability of the testis. In all species, the rate-limiting step in androgen biosynthesis is the conversion of cholesterol to pregnenolone by P450scc. In addition to this important enzyme, another protein, steroidogenic acute regulatory (StAR) protein, appears to transfer cholesterol from cellular stores to the inner mitochondrial membrane, where cholesterol is enzymatically converted to pregnenolone by cytochrome P450scc (Clark et al, 1994; Stocco and Clark, 1996). Few experimental studies involving the administration of endocrine disruptors have focused on StAR. A study has reported that the long-term administration of a plant estrogen (soy-phytoestrogen)-containing diet to adult rats reduces the concentration of testosterone, but not that of StAR (Weber et al, 2001). However, in this study, the level of StAR mRNA expression was increased in the 6-week-old offspring from the PCB126-administered group. The plasma testosterone level in the 3-week-old offspring from the PCB126-administered group was decreased, but that in the 6-week-old offspring did not differ from that in the control offspring, suggesting that the increase in the level of StAR mRNA expression was involved in the restoration of testosterone. When newborn mouse testes were cultured with PCB126, P450scc mRNA expression was significantly down-regulated by PCB126 (Fukuzawa et al, 2003). However, in this study, the administration of each PCB did not change the level of testicular P450scc mRNA expression, suggesting that the testosterone concentration changes observed after the transplacental passage of PCB to embryos and newborns were not because of the changes in the early stages of steroidogenesis.
We measured the expression levels of the mRNAs of hormone-synthesizing
enzymes 3ß-HSD and P45017 and found that the expression
levels of these mRNAs were unchanged at 3 and 6 weeks after birth, when
testosterone levels should normally have been decreased. Leydig cells bear
androgen receptors (Bremner et al,
1994), whose expression is inhibited at puberty
(Shan et al, 1995). In
immature animals, testosterone is an important autocrine regulator in the
differentiation of Leydig cells. Treatment of undifferentiated Leydig cells
with androgen and LH in vitro increases their testosterone-synthesizing
ability (Hardy et al, 1990). An increase in endogenous LH exerts a positive control on the membrane
receptor and steroid synthesis in Leydig cells
(Dufau, 1988;
Nishihara et al, 1988;
Tang et al, 1998). In
contrast, in the mature testes, androgen is believed to limit the biosynthesis
of androgen by inhibiting the activity of steroid-synthesizing enzymes and
their gene expression. In an in vitro study with mature Leydig cells,
testosterone treatment inhibited the activity of 3ß-HSD
(Ruiz de Galarreta et al,
1983) and P45017
(Darney et al, 1996). Plasma
testosterone levels rose rapidly until 45 days postnatally, thereafter
increasing gradually or flattening out
(Mack et al, 2000). Daily
injection of Aroclor 1242 to mothers during days 0 through 21 after
parturition caused a lower volume of Leydig cells and a lower level of LH in
pups (Kim et al, 2001). In
this study, maternal PCB administration decreased the area ratio of Leydig
cells/testis in the testes of 3-week-old offspring. When plasma testosterone
levels were decreased in the 3- and 6-week-old offspring from
PCB169-administered rats, LH levels were decreased compared with controls.
These low levels of testosterone and LH presumably retarded the
differentiation of Leydig cells. However, it is also possible that, at 15
weeks after birth, the Leydig cells in the offspring from PCB169-administered
rats had undergone differentiation to some extent and had acquired the ability
to secrete large amounts of testosterone with increased expression levels of
3ß-HSD and P45017.
Testosterone and its 5-reduced metabolite,
5-dihydrotestosterone (DHT), both interact with the AR to promote
androgen-dependent gene transcription. However, DHT is a more potent androgen
than testosterone because of its increased affinity for the AR; therefore, DHT
is assumed to amplify the androgen response when testosterone levels are low
(Grino et al, 1990;
Zhou et al, 1995).
5-Reductase 1, one of the isoforms of 5-reductase, was the
predominant isoform in the pubertal and adult rat testis, with both isoforms
being lower in the adult testis (Pratis et
al, 2000). Pratis et al
(2003) concluded that
testosterone negatively regulated 5-reductase 1 mRNA, resulting in an
increase in the metabolism of testosterone to a more potent metabolite, DHT.
In this study, in the 6-week-old offspring from the PCB169-administered group,
the plasma testosterone level was decreased, but the level of
5-reductase 1 mRNA expression remained unchanged, whereas, in the
15-week-old offspring, the plasma testosterone level was increased, and the
level of 5-reductase 1 mRNA expression was decreased. Thus, we
speculate that the high plasma testosterone level in the 15-week-old offspring
from the PCB169-administered group was because of the decrease in
5-reductase 1 mRNA, resulting in the inhibition of the conversion of
testosterone to DHT and the recovery of spermatogenesis.
In utero and lactational exposure of rats to 2 kinds of PCB exerted different inhibitory effects. PCB126 reduced the testosterone concentration at 3 weeks after birth, mainly through the inhibitory effect on the higher central nervous system, but exerted little or no inhibitory effects at 6 weeks after birth. On the other hand, PCB169 reduced the testosterone concentration at 3 and 6 weeks after birth, indicating a stronger inhibitory effect on spermatogenesis, via the inhibition of the pituitary-testicular axis; however, at 15 weeks after birth, the mRNA for testicular steroid-synthesizing enzymes had undergone changes, resulting in increased testosterone levels. The 2 PCBs reduced the percentage of testicular Leydig cells at 3 weeks after birth, indicating the inhibition of Leydig cell differentiation. These results indicate that PCB169 has a stronger inhibitory effect on testicular function than PCB126.
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Acknowledgments |
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Footnotes |
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