Influence of Corn Oil and Diet on Reproduction and the Kidney in Female Sprague-Dawley Rats

Masako Sato*,1, Kazuyoshi Wada*, Hideki Marumo*, Tetsuji Nagao{dagger}, Kiyoshi Imai{dagger} and Hiroshi Ono{dagger}

* Safety Testing Laboratory and {dagger} Research Division, Food and Drug Safety Center, Hatano Research Institute, 729-5, Ochiai, Hadano, Kanagawa 257-8523, Japan

Received August 6, 1999; accepted March 6, 2000


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The purpose of this study was to investigate the influence of corn oil administration on gestation, parturition, and lactation in rats, in conjunction with diets differing in composition of nutrients. Rats were divided into two groups, each fed different commercial pellets for rodents, CA-1 or CE-2, different from each other mainly in the source of protein. Female Sprague-Dawley rats in both diet groups were administered 0 (untreated control), 2, or 10 ml corn oil/kg body weight by gavage during the premating period (2 weeks), the mating period, the gestation period, and the lactation period (until day 3 of lactation). Food consumption of both the 10 ml/kg corn oil groups was significantly reduced throughout the study. Body weight gain in the 10 ml/kg corn oil group fed the CA-1 diet was significantly reduced on days 0 through 4 of lactation. Neither mating nor fertility indices were affected, and no clinical signs were observed during the gestation period in any groups. Several dams in the 10 ml/kg corn oil group fed the CA-1 diet, however, showed abnormal conditions after parturition, and three dams became moribund. Pup viability was also reduced in this group. Histopathologic examination of the kidneys of dams in the 10 ml/kg corn oil group fed the CA-1 diet revealed severe lesions in the proximal tubular epithelium, i.e., necrosis and fatty degeneration. Females in any group fed the CE-2 diet showed neither abnormal condition after parturition nor any severe lesions in the kidney. These data show that the combination of corn oil and diet with a particular constitution may cause adverse effects on the renal tubules in pregnant and/or lactating rats, suggesting that corn oil gavage as a vehicle can be a confounding factor in the reproductive toxicity studies, depending on the diet.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a toxicity study, the dosing vehicle often constitutes a confounding factor in the evaluation of toxicity of the substance. Many studies have shown that the choice of vehicle can affect uptake, distribution, pharmacokinetics, and toxicity of chemicals (Condie et al., 1986Go; Eaton and Klaassen, 1995Go; Farooqui et al., 1995Go; Withey et al., 1983Go). Corn oil has been used as one of the most common vehicles to administer lipophilic chemicals to rodents in toxicity studies. Corn oil has about 60% polyunsaturated fatty acid; therefore, it is one of the oils that has been recommended as a replacement for saturated fat (Dupont et al., 1990Go). However, corn oil itself is a nutrient and may have some biologic effects on animals. The results of a chronic treatment study of corn oil in rats (NTP, 1994Go) and summary reports on carcinogenicity studies by corn oil gavage (Haseman et al., 1985Go; Haseman and Rao, 1992Go; Rao and Haseman, 1993Go) have shown that corn oil administration elevated the incidence of pancreatic acinar cell adenoma and reduced or delayed development of spontaneous leukemia in rats.

Diet is also an essential factor influencing biologic processes such as growth, reproduction, survival, and responses to xenobiotics (Clarke et al., 1977Go; Gaillard et al., 1977Go; Garland et al., 1989Go; National Research Council, 1995; Rao, 1996Go). Many investigators have reported that dietary factors altered the toxicity of various chemicals (Carrera et al., 1979Go; Gans, 1982Go; Hathcock, 1976Go; Meyer et al., 1978Go; Shively et al., 1986Go). In addition to the dosing vehicle, the diet that is fed to the animals is an important factor in toxicological studies.

Recently, we had a confusing experience in a reproductive and developmental toxicity study, using corn oil at a dose rate of 10 ml/kg/day as the vehicle, in which several female rats from both the treated and the vehicle control groups did not care for their pups. From the results of microscopic observations of major organs in the dams, it was noted that almost all of the dams that had neglected their pups had severe lesions in the kidney, i.e., necrosis of the proximal tubular epithelium. This severe damage of the kidney, however, was not observed in male rats dosed with the same volume of corn oil and fed the same diet. Consequently, the diet type was changed and the dosing volume of corn oil administered was reduced, and the incidence and severity of the kidney injuries in dams were decreased. Although it is well known that the physiology of the kidney changes during pregnancy and the lactation period (Kincaid-Smith, 1985Go; Lindheimer and Katz, 1985Go; Stock and Metcalfe; 1994), how corn oil and/or diet influenced the kidney of pregnant and lactating rats in these studies is unknown.

In this study, we evaluated whether corn oil gavage can affect the pregnant and lactational states in rats, given two different diets. In addition, histopathological examination of the kidney was performed to clarify whether the combination of corn oil and different diets may influence the maternal kidney during gestation and lactation.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals.
Female Sprague-Dawley rats (Crj:CD) 7 weeks of age were obtained from Charles River Japan, Inc. (Atsugi Breeding Center, Japan) and were randomly divided into two different diet groups, as shown below. Rats were individually housed in stainless-steel wire cages in a temperature- (24 ± 1°C), humidity- (55 ± 5%), and lighting- (12-h light/dark cycle) controlled room. From day 18 of gestation to autopsy (day 4 of lactation), female rats and pups were housed on stainless-steel floors with wood-chip bedding. Food and tap water were given ad libitum throughout the study. Male rats of the same strain and same age were also purchased for mating partners. These males were divided into two diet groups and were kept under the same conditions as the females.

Diets.
One-half of the rats of each sex were fed the CA-1 diet, and the other half were fed the CE-2 diets, both of which were closed-formula commercial pellets for rodents (CLEA Japan, Inc., Japan). The CA-1 had been developed for reproduction in inbred animals, and the CE-2 is widely used for reproduction, growth, and maintenance of rodents. Both diets have been used as the standard diet in the reproductive and developmental studies in our laboratory. The nutrient composition of the CA-1 and the CE-2 diets is shown in Table 1Go. Details of vitamin and mineral components of these diets are given in Table 2Go. These values for both diets are at adequate levels for growth, maintenance, and reproduction, as recommended by the National Research Council (1995). The principal difference in the two diets is the source of protein; the protein in CA-1 is mainly animal protein (white fish meal and animal liver), whereas the protein in CE-2 is mainly plant protein (soybean meal), according to the catalog of CLEA Japan, Inc. These two diets were not shown to be contaminated with bacterial and chemical contaminants.


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TABLE 1 Nutrient Composition of CA-1 and CE-2 Diets
 

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TABLE 2 Vitamin and Mineral Concentrations of CA-1 and CE-2 Diets
 
Study design.
After 1-week acclimatization, female rats in each diet group were divided into three groups of 16 animals by stratified randomization based on body weight. Rats in each group were administered 2 and 10 ml corn oil/kg body weight daily by gavage during the premating period (2 weeks), mating period (maximum 2 weeks), gestation period, and lactation period (until day 3 of lactation). Treatment volume of corn oil was determined based on body weights, which were measured weekly before mating, on day 0 of gestation, and day 0 of lactation. During the dosing period, all treatment was conducted between 9 A.M. and 12 P.M. Corn oil of chemical reagent grade was purchased from Nacalai Tesque, Inc. (Japan). Untreated females served as controls. All animals were examined at least once a day for general physical condition. Food consumption of female animals was measured at weekly intervals for the premating period (day 1 and 8 of premating).

For 2 weeks following the treatment period, each female was housed with one male within the same diet group until evidence of mating (presence of copulatory plug or sperm in a vaginal smear) was observed. In case of no evidence of mating for 2 weeks of the mating period, the females were sacrificed (see below). After mating had been noted, the females were caged individually. The day of mating was regarded as day 0 of gestation. Pregnant females were weighed and their food consumption recorded on days 0, 7, 14, and 20 of gestation. All pregnant females were allowed to deliver naturally, and day 0 of lactation was defined as the day on which all pups in a litter had been delivered. The confirmation of delivery was performed from 9 A.M. to 11 A.M. because of treatment time (from 9 A.M. to 12 P.M.). Dams were weighed and food consumption was recorded on days 0 and 4 of lactation. Litters were evaluated for the number of pups (live and dead), sexed, and weighed individually on days 0 and 4 of lactation. Visible physical abnormalities or abnormal demeanor of the pups was recorded during the lactation period.

Autopsy.
All adult females were exsanguinated under pentobarbital anesthesia on day 4 of lactation in dams, on day 25 of gestation in the case of mated females that did not deliver, and on the next day after the mating period in females that failed to copulate. Animals observed to be moribund during the course of the study were euthanized and autopsied. The uteri and ovaries were excised, and the numbers of corpora lutea and implantation sites were recorded. The kidneys, liver, and thymus of all females were weighed and preserved in 10% neutral buffered formalin. All pups were euthanized by ether and necropsied on day 4 of lactation. Pups found dead during the lactation period were also examined macroscopically.

Histopathologic examination of the kidney.
The kidneys of all adult females were examined microscopically. The fixed kidneys were embedded in paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin. The lesions of the kidneys were graded. The grading criteria were as follows: grade 0, no lesions; grade 1, very slight; grade 2, slight; grade 3, moderate; grade 4, severe.

Statistical evaluation.
Data obtained herein were analyzed, where appropriate, to detect the statistical significance of difference at p < 0.05 and p < 0.01. Two-way (diet and corn oil volume) analysis of variance (ANOVA) was used to analyze results for the body weight, food consumption, and reproductive indices. When necessary, an LSD post hoc analysis was used to evaluate more detail. If an interaction was indicated, mean comparisons were done within each diet group by one-way ANOVA. The frequency of each lesion in the kidneys was analyzed with Fisher's exact probability test for incidence and Mann-Whitney U test for trend of grade. Correlation between the grade of kidney lesions and reproductive index was performed using Spearman's rank correlation.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
General Condition of Animals
During the lactation period, 7 out of 16 dams in the 10 ml/kg corn oil group fed the CA-1 diet exhibited abnormalities in their general condition. In particular, 3 of these dams showed severe toxic signs such as soiled fur, hunchback position, piloerection, hypothermia, and decrease in movement on day 1 of lactation. These dams did not nurse their pups, and most of their pups died before day 1 of lactation. Considered moribund, the 3 dams were autopsied on the same day. Another 3 dams in this group had soiled fur or hypothermia and did not care for their pups; all their pups died during the lactation period. One of these dams was autopsied on day 3 of lactation and the other two dams were autopsied on day 4 of lactation. The last dam out of 7 dams that exhibited abnormalities in their general condition showed soiled fur and diarrhea on day 1 of lactation, but recovered on day 2 of lactation, and thereafter nursed her pups well. On the other hand, in the untreated control group and 2 ml/kg corn oil group fed the CA-1 diet, no females showed clinical abnormalities during the study. No dams in the CE-2 groups exhibited any abnormality.

Food Consumption and Body Weight Gain
Figure 1Go shows the food consumption of females in each group. Two-way ANOVA indicated significant diet and corn oil volume effects in each period of the study. Diet and corn oil volume interaction effects were also detected during the lactational period. Post hoc analysis indicated the mean food consumption in both 10 ml/kg corn oil groups were significantly lower (p < 0.01) than the relevant control group except for the lactational period. On days 0–4 of lactation, corn oil volume effects on mean food consumption were statistically significant in each diet group (one-way ANOVA, p < 0.01). No appreciable changes in food consumption were noted in the 2 ml/kg corn oil groups of both diet groups.



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FIG. 1. Food consumption in female rats fed the CA-1 diet (A), and CE-2 diet (B) throughout treatment period. Data are plotted as group means ± SD. **Statistical significance from control fed the same diets (post-hoc LSD test, p < 0.01). ## Statistical significance, (one-way ANOVA, p < 0.01).

 
Figure 2Go shows the body weight gain of adult females in each group. Two-way ANOVA indicated corn oil volume effect on days 1–8 of premating period (F2,90 = 4.02, p < 0.05) and on days 0–4 of lactation (F2,80 = 11.7, p < 0.0001), and diet effect on days 8–15 of premating period (F1,90 = 3.97, p < 0.05). There were also significant interaction effects on days 14–20 of pregnancy (F2,86 = 5.10, p < 0.01), but the one-way ANOVA which followed did not show significant effects of corn oil volume. Post hoc analysis indicated statistically significant decreases in the 10 ml/kg corn oil group fed the CA-1 diet on days 1–8 of the premating period (p < 0.05), and statistically significant decreases on days 0–4 of lactation in the 10 ml/kg corn oil group fed the CA-1 diet (p < 0.01) and in the 10 ml/kg corn oil group fed the CE-2 diet (p < 0.05) compared to the relevant control. Body weight gain in the both of the 2 ml/kg corn oil groups was comparable to the relevant control group throughout the study.



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FIG. 2. Body weight gains in female rats fed the CA-1 diet (A), and CE-2 diet (B) throughout treatment period. Data are plotted as group means ± SD. **Statistical significance from control fed the same diets (post-hoc LSD test, p < 0.01). *Statistical significance from control fed the same diets (post-hoc LSD test, p < 0.05).

 
Reproductive Findings
In the mating trial, indices of copulation and fertility were not affected in any group and no abnormality was found in the number of corpora lutea and implantation sites (data not shown). The number of pups born, the number of live pups, and their sex ratio (not shown) on day 0 of lactation did not differ between the treated and the control animals in either diet group (Table 3Go). On day 4 of lactation, the number of pups surviving and pup viability showed statistically significant differences with regard to diet (the number of pups surviving, F1,85 = 20.8, p < 0.0001; pup viability, F1,86 = 9,85, p < 0.01), corn oil volume (the number of pups surviving, F2,85 = 9.12, p < 0.001; pup viability, F2,86 = 7.30, p < 0.01), and interaction (the number of pups surviving, F2,85 = 11.5, p < 0.0001; pup viability, F2,86 = 8.27, p < 0.001) effects by two-way ANOVA. From further analysis (one-way ANOVA), both parameters were significantly different (p < 0.01) in the corn oil volume effects in rats fed the CA-1 diet. Loss of the entire litter was found only in the 10 ml/kg corn oil group fed the CA-1 diet, in 5 of 16 litters. During the lactation period, the total numbers of dead pups in the control, the 2 ml/kg, and the 10 ml/kg corn oil groups fed the CA-1 diet there were 12, 13, and 103, respectively. In contrast, the total numbers of dead pups in each group fed the CE-2 diet were 6, 2, and 9, respectively.


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TABLE 3 Reproductive and Developmental Indices
 
Necropsy Findings
Autopsy of the adult females revealed some pale and some dark-colored kidneys, small thymus, small spleen, and erosion in the stomach; soiled fur was observed as well in the 10 ml/kg corn oil group fed the CA-1 diet, especially in those rats sacrificed due to moribundity. Although six females in this group showed reduced thymus size, there were no significant effects of any treatment on absolute and relative organ weights (kidneys, liver, and thymus; data not shown). Some macroscopic changes (e.g., small thymus, pale-colored kidneys, and dilatation of the kidney pelvis) were found sporadically in all other groups including the control group.

External and visceral examination of pups that died during lactation or were killed on day 4 of lactation showed no abnormality, except for emaciation in dead pups from dams in the 10 ml/kg corn oil groups fed the CA-1 diet.

Histopathology
Histopathologic findings (Table 4Go, Fig. 3Go) of the kidneys in the 10 ml/kg corn oil groups fed the CA-1 diet showed severe epithelial necrosis and fatty degeneration of the proximal tubule. Basophilic tubules suggesting epithelial regeneration were observed as well. In comparison with the control group fed the same diet, both the incidence and the severity of necrosis (p < 0.05, p < 0.05), fatty degeneration (p < 0.05, p < 0.01), and basophilic epithelium of proximal tubules (p < 0.05, p < 0.05) were significantly increased in the 10 ml/kg corn oil groups fed the CA-1 diet. Females with severe fatty degeneration of proximal tubules tended to have both necrosis and basophilic tubules. The incidence, but not severity, of fatty change, which may be attributed to corn oil treatment, was significantly increased (p < 0.05) in the 2 ml/kg group fed the CA-1 diet and the 10 ml/kg group fed the CE-2 diet.


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TABLE 4 Histopathological Findings from the Kidneys of Female Rats
 


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FIG. 3. Kidney of female rat dosed with 10 ml/kg corn oil and fed the CA-1 diet, necropsied at day 4 of lactation. Necrosis and fatty degeneration of the proximal tubule epithelium were observed. Hematoxylin and eosin stain. Bar is equal to 50 µm.

 
Comparison of Kidney Lesion Severity and Reproductive Index
Table 5Go and Figure 4Go summarize the relationship between the number of pups born and the grade of kidney lesion mainly observed in dams. Table 5Go shows individual data on the number of pups born and major lesions of their dams' kidneys in the 10 ml/kg group fed the CA-1 diet. All dams showing necrosis in the kidneys delivered more than 14 pups. On the other hand, necrosis was not observed in dams delivering fewer than 12 pups. Dams delivering a large number of pups tended to have severe fatty degeneration in the proximal tubule epithelium. The fatty degeneration was observed in all groups; therefore, correlation between the grade of the fatty degeneration in the kidney and the number of pups born in all groups (Fig. 4Go) was performed. Positive correlations between the severity of the fatty degeneration and number of the pups born were observed in the 2 ml/kg ({rho} = 0.509, p < 0.05) and 10 ml/kg group fed the CA-1 diet ({rho} = 0.733, p < 0.01). In the other groups, the correlation was not observed.


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TABLE 5 Number of Pups Delivered and Severity of Selected Kidney Lesions in Individual Dams in the 10 ml/kg Corn Oil, CA-1 Diet Group
 


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FIG. 4. Relationship between grade of fatty degeneration in the proximal tubule epithelium and number of pups delivered in individual dams fed the CA-1 (A), and CE-2 diet (B). Nonpregnant females indicated by 0 for number of pups born.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study revealed that administration of corn oil at the usual dose rate of 10 ml/kg as a vehicle of a test agent to pregnant and lactating rats resulted in toxic effects on the kidney, according to diet. Female rats administered 10 ml/kg/day corn oil and fed the CA-1 diet for the 2-week premating period as well as the gestation and lactation periods were in abnormal general condition just after the delivery of their pups and were also found to have some severe lesions in the proximal tubules of the kidney. In dams administered the same dose of corn oil but fed the CE-2 diet, on the other hand, there were no remarkable adverse influences on the kidney and the viability of pups.

According to a study on acute oral toxicity of corn oil, capillary venous congestion, necrosis, and many droplets at the proximal and distal tubules were observed in the kidneys of rats that died (Boyd et al., 1969Go). These renal lesions observed in rats treated with huge amounts of corn oil resembled our results. In addition to histopathologic alteration of the kidney by corn oil, Bachmann and Weber (1990) reported altered renal function. In female rats given a corn oil-enriched diet for 4 weeks, energy metabolism in the kidney changed, and ATP content in the kidney decreased markedly. Therefore, the kidney lesions observed in this study may be induced by corn oil administration, and it seems that the CA-1 diet enhances corn oil toxicity.

Food consumption of rats given 10 ml/kg corn oil in both diet groups was significantly lower than the controls throughout the treatment period, and the rats consumed approximately 70% of the corresponding control value. Moreover, less CA-1 diet was consumed than CE-2 diet by comparison between the groups treated with same dose of corn oil. It can be concluded that rats given 10 ml/kg corn oil and fed the CA-1 diet had the worst nutritional status among all experimental groups.

There are many reports about dietary fiber-altered toxicity of various chemicals (Chadwick et al., 1978Go; Kritchevsky, 1977Go; Wise and Gilburt, 1980Go). Although dietary fiber is not a nutrient because it passes unchanged though the intestine, dietary fiber may have influences on metabolism of xenobiotics (Johansson, 1970Go; Morgan et al., 1974Go). The CA-1 diet contains less fiber than the CE-2 diet, and food consumption of CA-1 was reduced compared with that of CE-2. This fiber deficiency may be one of the reasons for enhancement of corn oil toxicity in rats treated with 10 ml/kg corn oil and fed the CA-1 diet.

In the kidneys of rats treated with 10 ml/kg corn oil and fed the CA-1 diet, basophilic change of the proximal tubules was frequently observed, which is thought to be regeneration from injury or necrosis (Smith et al., 1972Go). Furthermore, chronic changes, i.e., fibrosis or the degeneration of the basement membrane in the proximal tubules, were not found in these kidneys. The three dams that showed severe changes in general condition were necropsied on day 1 of lactation, and the other dams were necropsied on day 3 or 4 of lactation. According to the above evidence, it is suggested that the necrosis of the proximal tubules occurred during the gestation period.

As severe damage of the kidney was not observed in nonpregnant female and male rats dosed with 10 ml/kg corn oil during 6 weeks and fed the CA-1 diet (unpublished data), pregnancy may be one of the factors increasing the toxicity of corn oil. During the late gestation period, rat fetuses are rapidly growing, and their nutritional requirements are increasing (Morriss et al., 1994Go). In this study, dams delivering relatively larger numbers of pups had more severe lesions of the kidneys among the dams treated with corn oil and fed the CA-1 diet. The nutrition required by a large number of fetuses may also exacerbate the corn oil toxicity in dams fed the CA-1 diet. The conditions observed in these dams resemble the ketotic state during pregnancy, which is characterized by fatty degeneration of the kidney (Smith et al., 1972Go). In addition to this gestational burden, the stress of parturition and lactation may become a trigger for corn oil toxicity, thus causing its adverse effects to arise after parturition.

From the results of the autopsies of pups, it appears that corn oil may have no direct effects on development of fetuses and pups under the conditions of our study. The pup viability from dams treated with 10 ml/kg corn oil and fed the CA-1 diet was reduced; however, the exacerbation of the condition of these dams may have resulted in the reduction in the viability of pups.

In the safety evaluation of chemicals, adjustment of dosage volume by recently measured body weights is recommended. Because a fixed volume was applied during the gestation period in this study, the dosage volume was decreasing below the recommended volume as body weights of the pregnant rats were increasing. When dosage volume changes by recently measured body weight, administration of less than 10 ml/kg of corn oil in rats fed the CA-1 diet may raise the corn oil toxicity.

The mechanism of nephropathy occurring in the gestational and lactational rats in the present study remains to be elucidated. We would expect further experiments to resolve the remaining questions of nephrotoxicity by corn oil gavage in gestational and lactational rats, e.g., histopathologic examination of the kidneys of pregnant rats, the regulation of number of fetuses by hemisalpingectomy, or modification of ingredients in the diet, such as fiber. Thus, corn oil used as a vehicle may become a confounding factor in reproductive toxicity studies, depending on the diets fed to the experimental animals. Moreover, daily administration of 10 ml/kg of corn oil by gavage, especially to pregnant rats, is not recommended, even if corn oil is a convenient vehicle.


    ACKNOWLEDGMENTS
 
The authors gratefully acknowledge Dr. Mariko Shirota and Dr. Ryo Ohta for their helpful discussions, and the help of Mr. Chiaki Watanabe, Dr. Makiko Kuwagata, Ms. Aki Matsumoto, Mr. Jiro Azegami, and Ms. Hiroko Inada. We also gratefully acknowledge Dr. Masayoshi Kanisawa for pathology support and review of the manuscript. This study was supported by the Japanese Ministry of Health and Welfare.


    NOTES
 
1 To whom correspondence should be addressed. Fax: +81-463-82-9627. E-mail: MASAcha{at}aol.com. Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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