목 적 흰쥐를 대상으로 N,N-dimethylformamide (DMF)가 생식기능과 발생에 미치는 독성을 확인하고, 그와 관련된 요인들을 조사하여, DMF에 의한 생식 및 발생독성의 기전을 이해하는데 필요한 기초 자료로써 활용하고자 본 연구를 수행하였다. 방 법 실험동물은 Sprague-Dawley 흰쥐 암수 각각 20 마리씩, 40 마리를 사용하였다. DMF 투여농도에 따라 4개의 실험군(n=5)으로 구분하였으며, 음용수에 혼합하여 각각 0, 1000, 4000, 8000 ppm으로 7주간 투여하였다. 발생독성연구를 위하여 임신된 흰쥐(GD8) 9 마리를 0, 4000, 8000 ppm 실험군(n=3)으로 구분하였고, 노출기간은 임신 10일부터 19일 까지였다. 모든 실험동물에 대하여 연구기간동안 체중, 음용수 섭취량, DMF의 대사산물인 N-methylformamide (...
목 적 흰쥐를 대상으로 N,N-dimethylformamide (DMF)가 생식기능과 발생에 미치는 독성을 확인하고, 그와 관련된 요인들을 조사하여, DMF에 의한 생식 및 발생독성의 기전을 이해하는데 필요한 기초 자료로써 활용하고자 본 연구를 수행하였다. 방 법 실험동물은 Sprague-Dawley 흰쥐 암수 각각 20 마리씩, 40 마리를 사용하였다. DMF 투여농도에 따라 4개의 실험군(n=5)으로 구분하였으며, 음용수에 혼합하여 각각 0, 1000, 4000, 8000 ppm으로 7주간 투여하였다. 발생독성연구를 위하여 임신된 흰쥐(GD8) 9 마리를 0, 4000, 8000 ppm 실험군(n=3)으로 구분하였고, 노출기간은 임신 10일부터 19일 까지였다. 모든 실험동물에 대하여 연구기간동안 체중, 음용수 섭취량, DMF의 대사산물인 N-methylformamide (NMF) 농도와 소변검사를 주기적으로 시행하였다. 혈액은 의료용 CO2가스로 마취시킨 후 채취하였으며, 생화학적 검사, 혈액학적 검사 등을 수행하였다. 생식독성 평가를 위해 월경주기(estrous cycle), 정자 수 및 기형, 생식 호르몬(testosterone, progesterone, estradiol) 및 생식기관의 병리조직학적 영향을 조사하였다. 발생독성 평가를 위해 황체 수, 태반 무게, 태아 수, 유산 등의 발생학적 자료와 태반의 병리조직학적 조사를 수행하였고, 태반과 태아의 성장에 관련된 PRL-군 호르몬 유전자와 PRL-군 유전자의 전사 조절인자인 Pit-1 a, b유전자의 발현을 조사하였다.
목 적 흰쥐를 대상으로 N,N-dimethylformamide (DMF)가 생식기능과 발생에 미치는 독성을 확인하고, 그와 관련된 요인들을 조사하여, DMF에 의한 생식 및 발생독성의 기전을 이해하는데 필요한 기초 자료로써 활용하고자 본 연구를 수행하였다. 방 법 실험동물은 Sprague-Dawley 흰쥐 암수 각각 20 마리씩, 40 마리를 사용하였다. DMF 투여농도에 따라 4개의 실험군(n=5)으로 구분하였으며, 음용수에 혼합하여 각각 0, 1000, 4000, 8000 ppm으로 7주간 투여하였다. 발생독성연구를 위하여 임신된 흰쥐(GD8) 9 마리를 0, 4000, 8000 ppm 실험군(n=3)으로 구분하였고, 노출기간은 임신 10일부터 19일 까지였다. 모든 실험동물에 대하여 연구기간동안 체중, 음용수 섭취량, DMF의 대사산물인 N-methylformamide (NMF) 농도와 소변검사를 주기적으로 시행하였다. 혈액은 의료용 CO2가스로 마취시킨 후 채취하였으며, 생화학적 검사, 혈액학적 검사 등을 수행하였다. 생식독성 평가를 위해 월경주기(estrous cycle), 정자 수 및 기형, 생식 호르몬(testosterone, progesterone, estradiol) 및 생식기관의 병리조직학적 영향을 조사하였다. 발생독성 평가를 위해 황체 수, 태반 무게, 태아 수, 유산 등의 발생학적 자료와 태반의 병리조직학적 조사를 수행하였고, 태반과 태아의 성장에 관련된 PRL-군 호르몬 유전자와 PRL-군 유전자의 전사 조절인자인 Pit-1 a, b유전자의 발현을 조사하였다.
Objectives. We sought to understand the mechanisms of the reproductive and developmental toxicity of N,N-dimethylformamide (DMF) by investigating related factors. Methods. Sprague-Dawley (SD) rats were used (20 males, 20 females). Nine time-mated SD rats were used for the developmental study. In the...
Objectives. We sought to understand the mechanisms of the reproductive and developmental toxicity of N,N-dimethylformamide (DMF) by investigating related factors. Methods. Sprague-Dawley (SD) rats were used (20 males, 20 females). Nine time-mated SD rats were used for the developmental study. In the dose-range trials, DMF was administered at 0, 1000, 4000, and 8000 ppm (n = 5 each) in drinking water for 7 weeks. Pregnant rats were administered DMF at 0, 4000, and 8000 ppm (n = 3 each) in drinking water from gestational day 10 to 19. During the experimental period, body weight, water consumption, urinary N methylformamide (NMF) concentration, and urine chemistry were analyzed every 3?5 days. Hematological and biochemical analyses were performed using blood obtained at necropsy. For the reproductive toxicity study, estrous cyclicity, sperm count and abnormalities, levels of reproductive hormones, and the histopathology of reproductive organs were evaluated. For the developmental toxicity study, placental weights, fetal weights, numbers of corpora lutea, numbers of live fetuses, pre- and post-implantation losses, the histopathology of the placenta, and gene expression of placental PRL-family hormones and Pit-1 a, b, trans-acting factors of the PRL-family hormones genes were evaluated. Results. There was a significant dose-related decrease in weight gain in male rats (p<0.05). In non-pregnant female rats, weight gains in the 4000 and 8000 ppm groups were significantly decreased relative to the controls (p<0.05). In pregnant female rats, a trend toward a decrease in weight gain was observed in a relation to exposure dosage, but it was not statistically significant. No significant differences were observed in chemistry, hematology, or urinalysis in any experimental group. In male rats, the mean weights of livers in the exposed groups were lower than those of the controls, but the difference was statistically significant only in the 4000 ppm group (p<0.05). In non-pregnant female rats, there was no significant difference in the mean weights of livers in exposed groups compared with the controls. In the histopathological study of livers, decreases in cellular organelles such as ribosomes and rough surface endoplasmic reticulum and changes in morphology and the arrangement in some hepatocytes were observed in DMF exposed groups. In the reproductive toxicity study, there was a significant lengthening of the estrous cycle in the 8000 ppm group relative to controls (p<0.05). Significant decreases in spermatid counts were observed in all groups exposed to DMF relative to controls. In the 8000 ppm group, the numbers of bent-tailed sperm and small headed sperm were significantly higher than in the control group (p<0.05). In male rats, testosterone levels in exposed groups were lower than in controls, but there was statistical significance only in the 4000 ppm group (p<0.05). No significant difference was observed in progesterone or estradiol levels in non-pregnant female rats. In the histopathological study of the testis, decreased and abnormal spermatids, atrophy of the seminiferous tubules, and decreased numbers of Leydig cells were observed in DMF-exposed groups. In the developmental toxicity study, there were significant dose-related decreases in placental weight, fetal weight, number of corpora lutea, number of implantation sites, and number of live fetuses (p<0.05). There was a significant trend toward an increase in the number of resorptions and dead fetuses and percentages of pre-implantation and post-implantation losses in relation to exposure dosage. In the histopathological study of the placenta, decreased cytotrophoblasts and increased fibroblasts were observed in DMF-exposed groups. In assays of gene expression of PRL-family hormones related to development and growth of the fetus and placenta, the expression of PL-II, Iv, and PLP A, B, and C genes was suppressed in DMF-exposed groups (p<0.05). Pit-1 a and b, which are transcription-regulating factors of the PRL-family hormone genes, were also suppressed in DMF-exposed groups (p<0.05). Conclusions. The toxicity of DMF, causing decreased weight gain and injury to hepatocytes, was confirmed. The reproductive toxicity of DMF was identified by the prolongation of the estrous cycle, decreased sperm count, increased abnormal sperm, and histopathological changes in the testis. The developmental toxicity of DMF was identified by decreased placenta and fetus weights and numbers of live fetus, increased pre- and post-implantation losses, and decreased gene expression of PRL-family hormones and Pit-1 a and b. We suggest that the toxicity is the result of disturbances of reproductive hormones caused by the anti-estrogenic effects of DMF, resulting in the suppression of gene expression and interference with the development and growth of the placenta and fetus.
Objectives. We sought to understand the mechanisms of the reproductive and developmental toxicity of N,N-dimethylformamide (DMF) by investigating related factors. Methods. Sprague-Dawley (SD) rats were used (20 males, 20 females). Nine time-mated SD rats were used for the developmental study. In the dose-range trials, DMF was administered at 0, 1000, 4000, and 8000 ppm (n = 5 each) in drinking water for 7 weeks. Pregnant rats were administered DMF at 0, 4000, and 8000 ppm (n = 3 each) in drinking water from gestational day 10 to 19. During the experimental period, body weight, water consumption, urinary N methylformamide (NMF) concentration, and urine chemistry were analyzed every 3?5 days. Hematological and biochemical analyses were performed using blood obtained at necropsy. For the reproductive toxicity study, estrous cyclicity, sperm count and abnormalities, levels of reproductive hormones, and the histopathology of reproductive organs were evaluated. For the developmental toxicity study, placental weights, fetal weights, numbers of corpora lutea, numbers of live fetuses, pre- and post-implantation losses, the histopathology of the placenta, and gene expression of placental PRL-family hormones and Pit-1 a, b, trans-acting factors of the PRL-family hormones genes were evaluated. Results. There was a significant dose-related decrease in weight gain in male rats (p<0.05). In non-pregnant female rats, weight gains in the 4000 and 8000 ppm groups were significantly decreased relative to the controls (p<0.05). In pregnant female rats, a trend toward a decrease in weight gain was observed in a relation to exposure dosage, but it was not statistically significant. No significant differences were observed in chemistry, hematology, or urinalysis in any experimental group. In male rats, the mean weights of livers in the exposed groups were lower than those of the controls, but the difference was statistically significant only in the 4000 ppm group (p<0.05). In non-pregnant female rats, there was no significant difference in the mean weights of livers in exposed groups compared with the controls. In the histopathological study of livers, decreases in cellular organelles such as ribosomes and rough surface endoplasmic reticulum and changes in morphology and the arrangement in some hepatocytes were observed in DMF exposed groups. In the reproductive toxicity study, there was a significant lengthening of the estrous cycle in the 8000 ppm group relative to controls (p<0.05). Significant decreases in spermatid counts were observed in all groups exposed to DMF relative to controls. In the 8000 ppm group, the numbers of bent-tailed sperm and small headed sperm were significantly higher than in the control group (p<0.05). In male rats, testosterone levels in exposed groups were lower than in controls, but there was statistical significance only in the 4000 ppm group (p<0.05). No significant difference was observed in progesterone or estradiol levels in non-pregnant female rats. In the histopathological study of the testis, decreased and abnormal spermatids, atrophy of the seminiferous tubules, and decreased numbers of Leydig cells were observed in DMF-exposed groups. In the developmental toxicity study, there were significant dose-related decreases in placental weight, fetal weight, number of corpora lutea, number of implantation sites, and number of live fetuses (p<0.05). There was a significant trend toward an increase in the number of resorptions and dead fetuses and percentages of pre-implantation and post-implantation losses in relation to exposure dosage. In the histopathological study of the placenta, decreased cytotrophoblasts and increased fibroblasts were observed in DMF-exposed groups. In assays of gene expression of PRL-family hormones related to development and growth of the fetus and placenta, the expression of PL-II, Iv, and PLP A, B, and C genes was suppressed in DMF-exposed groups (p<0.05). Pit-1 a and b, which are transcription-regulating factors of the PRL-family hormone genes, were also suppressed in DMF-exposed groups (p<0.05). Conclusions. The toxicity of DMF, causing decreased weight gain and injury to hepatocytes, was confirmed. The reproductive toxicity of DMF was identified by the prolongation of the estrous cycle, decreased sperm count, increased abnormal sperm, and histopathological changes in the testis. The developmental toxicity of DMF was identified by decreased placenta and fetus weights and numbers of live fetus, increased pre- and post-implantation losses, and decreased gene expression of PRL-family hormones and Pit-1 a and b. We suggest that the toxicity is the result of disturbances of reproductive hormones caused by the anti-estrogenic effects of DMF, resulting in the suppression of gene expression and interference with the development and growth of the placenta and fetus.
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