Toxicological Sciences 54, 416-423 (2000)
Copyright © 2000 by the Society of Toxicology
Reproductive Toxicity of 1-Bromopropane, a Newly Introduced Alternative to Ozone Layer Depleting Solvents, in Male Rats
* Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan;
National Institute of Industrial Health, Kanagawa, Japan;
Institute for Laboratory Animal Experiments, Nagoya University School of Medicine, Nagoya, Japan;
§ Safety Assessment Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd., Mie, Japan;
¶ Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan; and
|| Nagoya University Graduate School of Bioagricultural Sciences, Nagoya, Japan
Received August 31, 1999; accepted November 24, 1999
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1-Bromopropane has been newly introduced as an alternative to ozone-depleting solvents. We aimed to clarify its dose-dependent reproductive toxicity in male rats. Thirty-six Wistar male rats were randomly divided into 4 groups of 9. The groups were exposed to 200, 400, or 800 ppm 1-bromopropane or only fresh air, 8 h per day for 12 weeks. Epididymal sperm indices were evaluated after a 12-week exposure. The testes, epididymides, seminal vesicle, prostate, and other organs were weighed and examined histopathologically. Spermatogenic cells, in stage VII seminiferous tubules, and retained spermatids, at the basal region of stages IX–XI seminiferous epithelium, were counted. Plasma testosterone levels were measured by radioimmunoassay. The testicular weight did not significantly change, but the weight of epididymides, seminal vesicle, and prostate dose-dependently decreased. The weight of seminal vesicle decreased significantly at the lowest concentration of 200-ppm and over. 1-Bromopropane induced a dose-dependent decrease in the epididymal sperm count and in motility, as well as an increase in tailless sperm and sperm with an immature head shape. The spermatogonia, preleptotene spermatocytes, pachytene spermatocytes, and round spermatids did not decrease significantly at stage VII. Retained, elongated spermatids near the basement membrane at the postspermiation stages IX–XI increased dose-dependently. Plasma testosterone levels significantly decreased at the 800-ppm dosage. 1-Bromopropane caused failure of spermiation. Its reproductive toxicity is different from that of 2-bromopropane, which specifically impairs spermatogonia. Thus, this solvent may have serious reproductive toxic effects in men, and should be used very cautiously in the workplace.
Key Words: 1-bromopropane; reproductive toxicity; alternative to chlorofluorocarbons; spermiation failure; retention of elongated spermatid; spermiogenesis; Sertoli cell; testosterone; seminal vesicle; banana-like head.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Efforts are underway to curtail production of chlorofluorocarbons and to recover them so as to prevent destruction of theozone layer. Some specific chlorofluorocarbons and 1,1,1-trichloroethane have been banned from production in industrially developed countries since January 1, 1996. Consequently, many kinds of substitutes have been introduced into the workplace. 1-Bromopropane and 2-bromopropane came to be used as new alternatives to chlorofluorocarbons after most fluorinated and chlorinated hydrocarbons were ruled out because of their high ozone-depleting potency or their known toxic effects on workers. 1-Bromopropane and 2-bromopropane seemed to be promising solvents because they had less ozone-depleting potency, were nonflammable, and had high volatility as cleaning agents in the workplace. However, azoospermia or oligozoospermia and amenorrhea, which were sometimes associated with anemia, were recently found in the workers exposed to 2-bromopropane (Kim et al., 1996
; Park et al., 1997). We (Ichihara et al., 1996, 1997; Kamijima et al., 1997a,b; Nakajima et al., 1997a,b; Yu et al., 1999) and another group (Lim et al., 1997; Yu et al., 1997) clarified the dose-dependent adverse effect of 2-bromopropane on reproductive and hematopoietic organs in rats. We found a decrease in all seprmatogenic-type cells, including spermatogonia, after a 9-week exposure and a decrease in spermatogonia and spermatocytes after 11-days of exposure to 2-bromopropane. 2-Bromopropane was revealed to have a specific toxicity to spermatogonia in the testis (Omura et al., 1999, 1997a,b) and oocytes in primordial follicles in the ovary (Yu et al., 1999). We also clarified a possible dose-dependent effect on hematopoiesis in workers exposed to 2-bromopropane at rather low concentrations (Ichihara et al., 1999a). On the other hand, the adverse health effects of 1-bromopropane are not well known, because it is a newly introduced solvent. Recently, 1-bromopropane has come to be used more and more, and the number of workers exposed to it is increasing. Some 645 tons of 1-bromopropane were sold in 1998 in Japan, where it was used as a cleaning agent for metal, precision instruments, electronics, optical instruments, and ceramics (according to the data from the Association of Bromopropane Producers in Japan). Its effects on the reproductive organs have been of concern because its isomer, 2-bromopropane, has a serious reproductive toxicity.
The present experiment aimed to clarify the dose-dependent reproductive toxicity of 1-bromopropane in male rats. Parts of this study were presented at the 71st and 72nd Annual Meetings of the Japan Society for Occupational Health (Ichihara et al., 1998, 1999b).
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Animals and exposure.
A total of 36 specifically pathogen-free, male, 9-week-old Wistar rats were purchased from Shizuoka Laboratory Animal Center, Japan. They were housed and acclimated to new circumstances for one week, and randomly divided into 4 groups of 9 each. Food and water were provided ad libitum. The animal room was controlled with a 12-h light-dark cycle (lights on at 900 h and off at 2100 h) and with room temperature of 23–25° and relative humidity at 57–60%. Body weight was obtained between 10:00 and 11:00 A.M. once a week.
The 4 groups were exposed to either 200, 400, or 800 ppm of 1-bromopropane or fresh air. The maximum concentration was 800 ppm because our previous study (Yu et al., 1998) showed that rats exposed to 1000 ppm of 1-bromopropane were debilitated after 4 weeks. The inhalation exposure was conducted from 1400 to 2200 h. The inhalation exposure system used in the present study has been described previously (Ichihara et al., 1997; Takeuchi et al., 1989). In brief, the regulated volume of 1-bromopropane was evaporated at room temperature and mixed with a larger volume of clean air to achieve the target concentrations. The vapor concentrations of 1-bromopropane in the chamber were measured every 10 s by gas chromatography and controlled to within ±5% of the target concentration by means of a personal computer. The mean concentration of levels measured every 10 s for 8 h was taken for the value on a given day. This was then averaged over 12 weeks in order to obtain the mean and standard deviations, and the daily gas concentrations in the 3 chambers were measured at 208 ± 15, 412 ± 24, and 821 ± 38 ppm, respectively. The 1-bromopropane (99.81% purity) was kindly supplied by Tosoh Co., Ltd., Japan. The Japanese law concerning protection and control of animals and the Guide of Animal Experimentation of the Nagoya University School of Medicine were followed throughout the experiments.
Epididymal sperm count, motility, tailless sperm ratio, and morphological abnormality of sperm head.
After 12 weeks' of exposure, the rats were weighed, and, under pentobarbital anesthesia, were killed by collecting all blood through the abdominal aorta. Epididymal sperm count and motility were evaluated according to our previous studies (Ichihara et al., 1996, 1997). Sperm were collected as quickly as possible after the rat was killed. The sperm suspension was prepared by mincing the right cauda epididymidis in 2.5 ml of Hank's solution kept at 37°C, pipetting the suspension and filtering it through gauze. A part of the fraction was diluted with Hank's solution kept at 37°C. Progressive or non-progressive motile sperm were counted on an erythrocytometer (Neubauer type) under a light microscope. Another fraction was diluted with saline containing 0.5% formalin for detemination of the sperm count. A smear was made on a glass slide, and the sperm shape was examined under a phase-contrast microscope. Tailless sperm and sperm with morphologically abnormal heads were counted. A total of 300 sperm were examined to count tailless sperm, and 300 sperm with tails were examined to count sperm with morphologically abnormal heads, which were classified as straight, banana-like, teratic, (amorphous or pyknomorphous), and "other" (unclassified), according to Mori et al. (1991). An intermediate type with characteristics of both a banana-like (blunt) head and straight head was classified as banana-like, because most banana-like heads were also more or less straight.
Organ weights and histopathological examinations.
The epididymides, testes, prostate, seminal vesicle, liver, kidneys, spleen, lungs, heart, adrenal glands, thymus, pituitary gland and femur were dissected out of the rats at the end of the experiment, and were weighed, excluding the femur. The testes and the left epididymis were fixed in Bouin's solution and the other organs in 10% neutral buffered formalin for histopathological studies. The femur was decalcified after the fixation. The organs were embedded in paraffin and cut in 5-µm sections. Tissue sections of the testis were reacted with periodic acid-Schiff's reagent (PAS) and other organs were stained with hematoxylin and eosin (H-E).
Cell counts of spermatogenic cells and degenerating cells in seminiferous tubules.
Spermatogenic cells at stage VII were counted to evaluate the cellularity of spermatogenic cells in the testis, according to Omura et al. (1999). Twelve photomicrographs of stage VII seminiferous tubules were randomly taken under light microscope from one section of testis per rat with a digital camera (Fujix Digital Camera HC-300Z/CL, Olympus Japan Co., Ltd.). The digital pictures were printed out with a full-color, high-resolution digital printer (PICTROGRAPHY 3000, Fuji Film Japan Co., Ltd.). All of the spermatogonia, preleptotene spermatocytes, pachytene spermatocytes, round spermatids, and nuclei of Sertoli cells in the seminiferous tubule were counted. Spermatogonia, preleptotene spermatocytes, and nuclei of Sertoli cells were confirmed by direct observation under light microscope, because it was sometimes difficult to classify these cells on the print. We examined 12 seminiferous tubules per rat, because the digital camera could take only 12 pictures, making it easy to avoid counting of the same seminiferous tubules twice. We considered that 12 tubules was enough, because 12 was more than the 10 recommended in the review by Creasy (1997) and adopted in the original study by Omura et al. (1999). Degenerating pachytene spermatocytes and vacuoles or spaces in the seminiferous epithelium at stage VII were also counted. Elongated spermatid at stage VII were not counted because it was difficult to do so accurately. Retained, elongated spermatid and nuclei of Sertoli cells were counted in 12 round or ovoid seminiferous tubules at postspermiation stages (stages IX, X, and XI) in the same way. Retained, elongated spermatids near the lumen were not counted, because it was sometimes difficult to distinguish them from released spermatids in the lumen. Only retained and degenerating (probably phagocytized by Sertoli) elongated spermatids near the basement membrane were counted for quantitative evaluation. The criterion was that more than half of the profile should be in the basal one or two cell layers (layer of leptotene or pachytene spermatocytes). Stages of the cycle in rats were classified according to Russell et al. (1990). The numbers of the spermatogenic cells, degenerating cells, or vacuoles/spaces were expressed per tubule or per 100 Sertoli nuclei. A mean value of 12 tubules was treated as the representative value of each animal.
Hormone assay.
Plasma samples were stored at –80° until assayed for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Plasma testosterone levels were measured with a radioimmunoassay (RIA) kit for testosterone (Eiken Chemical, Tokyo). Ten µl of plasma was extracted with 2 ml of hexane-ethylether mixture (3:2). The detection limit was 1.2 ng/ml. LH and FSH concentrations in plasma were determined by a double antibody RIA with a rat LH RIA kit and FSH RIA kit provided by the National Hormone and Pituitary Program (Baltimore, MD), and were expressed in terms of NIDDK-rLH-RP-3 and NIDDK-rFSH-RP-2, respectively. The least detectable levels of LH and FSH were 0.16 ng/ml and 2.5 ng/ml for 50-µl samples, respectively.
Hematological examination.
The following hematologic parameters were determined: erythrocyte counts, hemoglobin concentration, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpusucular hemoglobin concentration (MCHC), total leukocyte count, and platelet count (with an F-800 Toa Microcell Counter, Toa Medical Electronics).
Statistical analysis.
Multiple comparisons were made between the exposure groups and the control using Dunnett's method following one-way analysis of variance (ANOVA). A probability (P) of <0.05 was accepted as statistically significant. The percentage values were converted by arcsine transformation before the above analysis. The log transformation was performed before ANOVA for the value of testosterone and the number of degenerating spermatids to equalize the variance, because the standard variation increased in proportion to the mean value. Root transformation was applied to the degenerating spermatocytes because the probability of degenerating spermatocytes was so low that it could be regarded as following the Poisson distribution.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Data on one control rat were excluded because it showed serious splenoma. The body weight and reproductive organ weights at the end of the experiment are shown in Table 1
. Body weight gain was suppressed dose-dependently in the exposed groups, but there was no suppression at 200 ppm. The absolute and relative testicular weights did not change significantly. The absolute weights of the epididymides, prostate, and seminal vesicle decreased dose-dependently. The relative weight of these organs showed the same tendency, but the change in prostate weight was not significant. The absolute and relative weight of the seminal vesicle significantly decreased, even at the lowest concentration of 200 ppm, compared to the control. The weights of the other organs were shown in Table 2. The absolute weight of the liver dose-dependently increased and that of the pituitary gland and spleen decreased, but those of the other organs did not show any significant changes (Table 2).
|
|
Dose-dependent deterioration was observed in epididymal sperm indices (Table 3
). The epididymal sperm count and percentage of motile sperm significantly decreased, and the percentage of tailless sperm significantly increased at 400 ppm or more. At the 800 ppm exposure level, significant increases in banana-like head, straight head, and unclassified head abnormalities were observed. Banana-like heads (Fig. 1) were overwhelmingly predominant among the head abnormalities in the 800-ppm group (Table 3). The sperm with teratic heads did not increase with dosage. The numbers of spermatogonia, spermatocytes, and round spermatids were not decreased by the treatment (Table 4). Degenerating pachytene spermatocytes were sparsely observed in stage VII seminiferous tubules of the 800-ppm group (Fig. 2). Such degeneration was not found in the seminiferous tubules at the other stages. The number of degenerating spermatocytes increased only at 800 ppm compared with the control (Table 5). No significant increase was observed in the number of spaces or vacuoles in the seminiferous epithelium at stage VII, but large vacuoles were found in only 2 rats of the 800-ppm group. No remarkable alterations were detected in interstitial (Leydig) cell populations, sizes, stainability, or other morphologies. Retained, elongated spermatids were frequently found both near the lumen and the more basal region of stages IX, X, and XI seminiferous tubules in the exposed groups (Fig. 3). The number of retained, elongated spermatids at the basal region increased dose-dependently (Table 6). In the epididymes of the 800-ppm group, the diameter of the duct cavity became smaller, the interstitial space was relatively wider, and the epithelial cells were seen to have a greater height than in the control. Neutrophil leukocytes or degenerated epithelial cell-like profiles were frequently found in the epididymal duct of the 800-ppm group. The prostate and seminal vesicle of the 800-ppm group showed smaller alveoli than the control. Many degenerated cells (probably epithelium-derived) were found in the vesicular cavity of the seminal vesicle in the 800-ppm group.
|
|
|
|
|
|
|
Many scanty areas, which suggest glycogen areas, were found in the cytoplasm of liver cells in the 800-ppm group. Fat droplets around the central vein of the 800-ppm group were smaller in size, number, and population than those of the control. No particular histopathological changes were observed in the other organs. Plasma testosterone was significantly decreased only in the 800-ppm group (Table 7
). No significant change was observed in LH and FSH values. Erythrocyte counts, hemoglobin concentration, hematocrit, total leukocyte counts and platelet counts did not change significantly, but MCV significantly increased at 800 ppm (3.1%, compared to the control), and MCHC significantly decreased at 400 ppm (2.4%) and 800 ppm (3.5%).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Exposure of male rats to 1-bromopropane reduced the epididymal sperm count and sperm motility and increased percentages of tailless sperm and sperm with abnormal heads. Degenerating pachytene spermatocytes increased only at the 800-ppm dosage level. However, this degeneration could not explain the 70% decrease in the epididymal sperm count in the 800-ppm group, because the cell count at stage VII did not show a decrease in round spermatids. A dose-dependent increase in retained, elongated spermatids at stages IX–XI might explain the epididymal sperm decrease. Such retained, elongated spermatids at the postspermiation stages were also reported in the testis of hypophysectomized rats (Russell et al., 1977), rabbits treated with fungizone (Swierstra et al., 1964
), or rats treated with various toxicants such as boric acid (Chapin et al., 1994; Ku et al., 1993; Linder et al., 1990; Treinen et al., 1991), cadmium (Hew et al., 1993), gallium arsenide (Omura et al., 1996), dibromoacetic acid (Linder et al., 1994a,b) or dichloroacetic acid (Linder et al., 1997; Toth et al., 1992). Retained, elongated spermatids at the postspermiation stages indicate failure of spermiation, which should be finished within stage VIII in normal rats. This failure would be related to a functional disorder of the Sertoli cell, since the spermiation process is mediated by cell contact between Sertoli cells and the spermatids. The present study did not show dose-dependent changes in the number of intracellular or intercellular vacuoles, which reflect Sertoli damage (Creasy, 1997), in the stage VII seminiferous epithelium. A time-course study is necessary to elucidate the involvement of possible Sertoli-cell damage with the degeneration of pachytene spermatocytes or spermiation failure.
Degenerating spermatocytes at stage VII at 800 ppm and retained spermatids at the postspermiation stages might be involved with hormonal changes, since hypophysectomy has been known to induce a degeneration of spermatocytes at stage VII and retention of step 19 spermatid (Russell et al., 1977). These changes were prevented by administration of LH and FSH (Russell et al., 1977). The present study showed a significant decrease in the plasma testosterone level at 800 ppm but not at 200 or 400 ppm. However, a dose-dependent decrease in the weight of the seminal vesicle might indicate a decrease in mean testosterone level at 200 ppm or higher, if the general presumption holds here that the weight of the seminal vesicle is specifically sensitive to the testosterone level (Hamilton 1990). We could not obtain data suggesting the involvement of change in gonadotropin secretion with a decrease in testosterone or testicular lesions. However, it should be noted that pentobarbital was used instead of decapitation, which sometimes causes hemolysis or contamination of blood with lymph, to evaluate hematotoxicity. Nazian (1988) showed that pentobarbital inhibited secretion of FSH, LH, or testosterone, while Morris and Knigge (1976) found it had no effect on LH. The present study also has the limitation of one-point blood sampling to evaluate the secretion of gonadotropins and testosterone, which are released in a pulsatile manner. Further studies are necessary to elucidate the involvement of gonadotropin secretion status with decreases in testosterone or Sertoli function.
The banana-like heads were similar to the heads of early-elongated spermatids. This morphological abnormality might be related to the immaturity of sperm. Mori et al. (1991) classified the straight heads or banana-like heads of sperm into an immature type in the rats exposed to ethylene oxide. In the rats administered gallium arsenide, spermiation failure was accompanied by an increase in sperm with straight heads (Omura et al., 1996). Such an increase would indicate the early release of elongated spermatids from Sertoli cells or a delay in the spermatid transformation process, which might also be related to a functional disorder of Sertoli cells.
The histopathological changes in the testis induced by 1-bromopropane are much different from those by 2-bromopropane, which causes severe testicular atrophy at 300 ppm for 9 weeks and an almost complete loss of germ cells at 1000 ppm for 9 weeks (Ichihara et al., 1996, 1997). As shown in the count of spermatogonia or spermatocytes at VII stage, 1-bromopropane does not have the severe toxicity toward spermatogonia which 2-bromopropane has. In addition, the present study also showed that 1-bromopropane had less hematopoietic toxicity than 2-bromopropane.
Kim et al. (1999) administered 50, 300, and 1800 ppm of 1-bromopropane to rats, 6 h/day, 5 days/week, for 8 weeks, and did not observe any reproductive toxicity. In their study, the 1-bromopropane exposure increased the relative testicular weight per body weight, but they did not mention absolute testicular weight nor did they examine the epididymal sperm, seminal vesicle, or prostate. They found cytoplasmic vacuolation in the hepatocytes around the central veins without dose-dependency, but did not observe 1-bromopropane-related morphological changes in the other organs or any significant changes in feed consumption, urinalysis, hematology, or serum biochemistry. In the present study, fat droplets around the central vein were found in the control group and they tended to decrease in the 800-ppm group.
The effects of 1- and 2-bromopropane on reproductive organs differed, but the lowest adverse effect levels (LOAEL) were almost the same as for the 200-ppm group in our experiments. 1-Bromopropane is a newly introduced solvent, and its toxic effects on exposed workers have not been reported to date. However, as seen in the intoxication cases of 2-bromopropane in Korea (Kim et al., 1996; Park et al., 1997), workers could be exposed to the solvent at higher concentrations when it is used in an open system in the workplace. Workers should thus be carefully protected from exposure to 1-bromopropane.
In conclusion, 1-bromopropane dose-dependently decreased the epidydimal sperm count and sperm motility, and increased tailless sperm and sperm with an immature head shape. It did not decrease the testicular weight, the number of spermatogonia, spermatocytes, or round spermatids at stage VII, but increased retained, elongated spermatids at the postspermiation stages IX–XI. These changes show that the main effect on reproductive organs of 1-bromopropane is inhibition of spermiation activity, in contrast to 2-bromopropane, which impairs spermatogonia. However, the lowest adverse effect levels of both 1- and 2-bromopropane are similar. Thus, this agent should be very cautiously used in the workplace, from the viewpoint of its possible male reproductive toxicity.
|
ACKNOWLEDGMENTS |
|---|
The authors thank Ms. Reiko Jose, Mr. Koichi Furuhashi, and Mr. Takashi Yamada for their generous assistance in counting spermatogenic cells. This study was partly supported by Grants 10470106 and 11670367 from the Ministry of Education, Science, Sports, and Culture, Japan.
|
NOTES |
|---|
1 To whom correspondence should be addressed at Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Fax: (81) (52) 744-2126. E-mail: gak{at}med.nagoya-u.ac.jp.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Chapin, R. E., and Ku, W. W. (1994). The reproductive toxicity of boric acid. Environ. Health Perspect. 102, 87–91.
Creasy, D. M. (1997). Evaluation of testicular toxicity in safety evaluation studies: The appropriate use of spermatogenic staging. Toxicol. Pathol. 25, 119–131.
Hamilton, D. W. (1990). Anatomy of mammalian male accessory reproductive organs. In Marshall's Physiology of Reproduction (G. E. Lamming, Ed.), pp. 691–746. Churchill Livingstone, Edinburgh.
Hew K. W., Ericson W. A., and Welsh, M. J. (1993). A single low-cadmium dose causes failure of spermiation in the rat. Toxicol. Appl. Pharmacol. 121, 15–21.[Web of Science][Medline]
Ichihara, G., Asaeda, N., Kumazawa, T., Tagawa, Y., Kamijima, M., Yu, X., Kondo, H., Nakajima, T., Kitoh, J., Yu, I. J., Moon, Y. H., Hisanaga, N., and Takeuchi, Y. (1996). Testicular toxicity of 2-bromopropane. J. Occup. Health 38, 205–206.
Ichihara, G., Asaeda, N., Kumazawa, T., Tagawa, Y., Kamijima, M., Yu, X., Kondo, H., Nakajima, T., Kitoh, J., Yu, I. J., Moon, Y. H., Hisanaga, N., and Takeuchi, Y. (1997). Testicular and hematopoietic toxicity of 2-bromopropane, a substitute for ozone layer-depleting chlorofluorocarbons. J. Occup. Health 39, 57–63.[Web of Science]
Ichihara, G., Ding, X., Yu, X., Wu, X., Kamijima, M., Peng, S., Jiang, X., and Takeuchi, Y. (1999a). Occupational health survey on workers exposed to 2-bromopropane at low concentrations. Am. J. Ind. Med. 35, 523–531.[Web of Science][Medline]
Ichihara, G., Yu, X., Eiji, S., Kitoh, J., Asaeda, N., Xie, Z., Wang, H., and Takeuchi, Y. (1998). Neurotoxicity of 1-bromopropane. Sangyo Eiseigaku Zasshi 40, 414 (Japanese).
Ichihara, G., Yu, X., Kitoh, J., Shibata, E., Asaeda, N., Yamada, T., Wang, H., Xie, Z., Kumazawa, T., Iwai, K., Maeda, K., Tsukamura, H., and Takeuchi, Y. (1999b). Histopathological changes of nervous system and reproductive organ and bloodbiochemical findingsin rats exposed to 1-bromopropane. Sangyo Eiseigaku Zasshi 41, 513 (Japanese).
Kamijima, M., Ichihara, G., Yu, X., Xie, Z., Kitoh, J., Tsukamura, H., Maeda, K., Nakajima, T., Asaeda, N., Hisanaga, N., and Takeuchi, Y. (1997a). Ovarian toxicity of 2-bromopropane in the non-pregnant female rat. J. Occup. Health 39, 144–149.
Kamijima, M., Ichihara, G., Yu, X., Xie, Z., Kitoh, J., Tsukamura, H., Maeda, K., Nakajima, T., Asaeda, N., Hisanaga, N., and Takeuchi, Y. (1997b). Disruption in ovarian cyclicity due to 2-bromopropane in the rat. J. Occup. Health 39, 3–4.
Kim, H. Y., Chung, Y. H., Jeong, J. H., Lee, Y. M., Sur, G. S., and Kang, J. K. (1999). Acute and repeated inhalation toxicity of 1-bromopropane in SD rats. J. Occup. Health 41, 121–128.
Kim, Y., Jung, K., Hwang, T., Jung, G., Kim, H., Park, J., Kim, J., Park, J., Park, D., Park, S., Choi, K., and Moon, Y. (1996). Hematopoietic and reproductive hazards of Korean electronic workers exposed to solvents containing 2-bromopropane. Scand. J. Work Environ. Health 22, 387–391.[Web of Science][Medline]
Ku, W. W., Chapin, R. E., Wine, R. N., and Gladen, B. C. (1993). Testicular toxicity of boric acid (BA): Relationship of dose to lesion development and recovery in the F344 rat. Reprod. Toxicol. 7, 305–319.[Web of Science][Medline]
Lim, C. H., Maeng, S. H., Lee, J. Y., Chung, Y. H., Kim, T. G., Park, J. H., Moon, Y. H., and Yu, I. J. (1997). Effects of 2-bromopropane on the female reproductive function in Sprague-Dawley rats. Ind. Health 35, 278–284.[Web of Science][Medline]
Linder, R. E., Klinefelter, G. R., Strader, L. F., Suarez, J. D., and Dyer, C. J. (1994a). Acute spermatogenic effects of bromoacetic acids. Fundam. Appl. Toxicol. 22, 422–430.[Web of Science][Medline]
Linder, R. E., Klinefelter, G. R., Strader, L. F., Suarez, J. D., and Roberts, N. L. (1997). Spermatotoxicity of dichloroacetic acid. Reprod. Toxicol. 11, 681–688.[Web of Science][Medline]
Linder, R. E., Klinefelter, G. R., Strader, L. F., Suarez, J. D., Roberts, N. L., and Dyer, C. J. (1994b). Spermatotoxicity of dibromoacetic acid in rats after 14 daily exposures. Reprod. Toxicol. 8, 251–259.[Web of Science][Medline]
Linder, R. E., Strader, L. F., and Rehnberg, G. L. (1990). Effect of acute exposure to boric acid on the male reproductive system of the rat. J. Toxicol. Environ. Health 31, 133–146.[Web of Science][Medline]
Mori, K., Kaido, M., Fujishiro, K., Inoue, N., Koide, O., Hori, H., and Tanaka, I. (1991). Dose-dependent effects of inhaled ethylene oxide on spermatogenesis in rats. Br. J. Ind. Med. 48, 270–274.[Medline]
Morris, M., and Knigge, K. M. (1976). The effects of pentobarbital and ether anesthesia on hypothalamic LH-RH in the rat. Neuroendocrinology 20, 193–200.[Medline]
Nakajima, T., Shimodaira, S., Ichihara, G., Asaeda, N., Kumazawa, T., Iwai, H., Ichikawa, I., Kamijima, M., Yu, X., Xie, Z., Kondo, H., and Takeuchi, Y. (1997a). 2-Bromopropane-induced hypoplasia of bone marrow in male rats. J. Occup. Health 39, 228–233.
Nakajima, T, Shimodaira, S., Ichihara, G., Asaeda, N., Kumazawa, T., Iwai, H., Ichikawa, I., Kamijima, M., Yu, X., Xie, Z., Kondo, H., and Takeuchi, Y. (1997b). Histopathological findings of bone marrow induced by 2-bromopropane in male rats. J. Occup. Health 39, 81–82.
Nazian, S. J. (1988). Serum concentrations of reproductive hormones after administration of various anesthetics to immature and young adult male rats. Proc. Soc. Exp. Biol. Med. 187, 482–487.[Medline]
Omura, M., Romero, Y., Zhao, M., and Inoue, N. (1997a). Histopathological changes of the testis in rats caused by subcutaneous injection of 2-bromopropane. J. Occup. Health 39, 234–239.
Omura, M., Romero, Y., Zhao, M., and Inoue, N. (1999). Histopathological evidence that spermatogonia are the target cells of 2-bromopropane. Toxicol. Lett. 104, 19–26.[Web of Science][Medline]
Omura, M., Tanaka, A., Hirata, M., Zhao, M., Makita, Y., Inoue, N., Gotoh, K., and Ishinishi, N. (1996). Testicular toxicity of gallium arsenide, indium arsenide, and arsenic oxide in rats by repetitive intratracheal instillation. Fundam. Appl. Toxicol. 32, 72–78.[Web of Science][Medline]
Omura, M., Zhao, M., Romero, Y., and Inoue, N. (1997b). Toxicity of 2-bromopropane on spermatogonia and spermatocytes. J. Occup. Health 39, 1–2.
Park, J. S., Kim, Y., Park, D. W., Choi, K. S., Park, S. H., and Moon, Y. H. (1997). An outbreak of hematopoietic and reproductive disorders due to solvents containing 2-bromopropane in an electronic factory: South Korea: Epidemiological Survey. J. Occup. Health 39, 138–143.
Russell, L. D., and Clermont, Y. (1977). Degeneration of germ cells in normal, hypophysectomized, and hormone-treated hypophysectomized rats. Anat. Rec. 187, 347–366.[Medline]
Russell, L., Ettlin, R., Sinha-Hikim, A., and Clegg, E. (1990). Histological and Histopathological Evaluation of theTestis, pp. 62–118. Cache River Press, United States.
Swierstra, E. E., Whitefield, J. W., and Foote, R. H. (1964). Action of amphotericin B (fungizone) on spermatogenesis in the rabbit. J. Reprod. Fertil. 29, 13–19.
Takeuchi, Y., Huang, J., Shibata, E., Hisanaga, N., and Ono, Y. (1989). A trial to automate an organic solvent exposure system for small animals. Jpn. J. Ind. Health 31, 722 (Japanese).
Toth, G. P., Kelty, K. C., George, E. L., Read, E. J., and Smith, M. K. (1992). Adverse male reproductive effects following subchronic exposure of rats to sodium dichloroacetate. Fundam. Appl. Toxicol. 19, 57–63.[Web of Science][Medline]
Treinen, K. A., and Chapin, R. E. (1991). Development of testicular lesions in F344 rats after treatment with boric acid. Toxicol. Appl. Pharmacol. 107, 325–335.[Web of Science][Medline]
Yu, I. J., Chung, Y. H., Lim, C. H., Maeng, S. S., Lee, J. Y., Kim, H. Y., Lee, S. J., Kim, C. H., Kim, T. G., Lim, C. H., Park, J. S., and Moon, Y. H. (1997). Reproductive toxicity of 2-bromopropane in Sprague Dawley rats. Scand. J. Work Environ. Health 23, 281–288.[Web of Science][Medline]
Yu, X., Ichihara, G., Kitoh, J., Xie, Z., Shibata, E., Kamijima, M., Asaeda, N., and Takeuchi, Y. (1998). Preliminary report on the neurotoxicity of 1-bromopropane, an alternative solvent for chlorofluorocarbons. J. Occup. Health 40, 234–235.
Yu, X., Kamijima, M., Ichihara, G., Li, W., Shibata, E., Hisanaga, N., and Takeuchi, Y. (1999). 2-Bromopropane causes ovarian dysfunction by damaging primordial follicles and their oocytes in female rats. Toxicol. Appl. Pharmacol. 159, 185–193.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Liu, S. Ichihara, S. S. Mohideen, U. Sai, J. Kitoh, and G. Ichihara Comparative Study on Susceptibility to 1-Bromopropane in Three Mice Strains Toxicol. Sci., November 1, 2009; 112(1): 100 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Hanley, M. R. Petersen, K. L. Cheever, and L. Luo N-Acetyl-S-(n-Propyl)-L-Cysteine in Urine from Workers Exposed to 1-Bromopropane in Foam Cushion Spray Adhesives Ann. Hyg., October 1, 2009; 53(7): 759 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Shimomura, K. Sakurai, M. Shimada, M. Hagiwara, M. Kato, and K. Furuhama Occurrence of headless sperms in adolescent rat urine Lab Anim, April 1, 2008; 42(2): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Banu, S. Ichihara, F. Huang, H. Ito, Y. Inaguma, K. Furuhashi, Y. Fukunaga, Q. Wang, J. Kitoh, H. Ando, et al. Reversibility of the Adverse Effects of 1-Bromopropane Exposure in Rats Toxicol. Sci., December 1, 2007; 100(2): 504 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Valentine, K. Amarnath, V. Amarnath, W. Li, X. Ding, W. M. Valentine, and G. Ichihara Globin S-Propyl Cysteine and Urinary N-Acetyl-S-Propylcysteine as Internal Biomarkers of 1-Bromopropane Exposure Toxicol. Sci., August 1, 2007; 98(2): 427 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Garner, C. Sloan, S.C.J. Sumner, J. Burgess, J. Davis, A. Etheridge, A. Parham, and B.I. Ghanayem CYP2E1-Catalyzed Oxidation Contributes to the Sperm Toxicity of 1-Bromopropane in Mice Biol Reprod, March 1, 2007; 76(3): 496 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. HANLEY, M. PETERSEN, B. D. CURWIN, and W. T. SANDERSON Urinary Bromide and Breathing Zone Concentrations of 1-Bromopropane from Workers Exposed to Flexible Foam Spray Adhesives Ann. Hyg., August 1, 2006; 50(6): 599 - 607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Meistrich, G. Wilson, K. L. Porter, I. Huhtaniemi, G. Shetty, and G. A. Shuttlesworth Restoration of Spermatogenesis in Dibromochloropropane (DBCP)-Treated Rats by Hormone Suppression Toxicol. Sci., December 1, 2003; 76(2): 418 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamada, G. Ichihara, H. Wang, X. Yu, K.-i. Maeda, H. Tsukamura, M. Kamijima, T. Nakajima, and Y. Takeuchi Exposure to 1-Bromopropane Causes Ovarian Dysfunction in Rats Toxicol. Sci., January 1, 2003; 71(1): 96 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, G. Ichihara, H. Ito, K. Kato, J. Kitoh, T. Yamada, X. Yu, S. Tsuboi, Y. Moriyama, R. Sakatani, et al. Biochemical Changes in the Central Nervous System of Rats Exposed to 1-Bromopropane for Seven Days Toxicol. Sci., May 1, 2002; 67(1): 114 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ichihara, J. Kitoh, X. Yu, N. Asaeda, H. Iwai, T. Kumazawa, E. Shibata, T. Yamada, H. Wang, Z. Xie, et al. 1-Bromopropane, an Alternative to Ozone Layer Depleting Solvents, Is Dose-Dependently Neurotoxic to Rats in Long-Term Inhalation Exposure Toxicol. Sci., May 1, 2000; 55(1): 116 - 123. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||