Embryo lethality and teratogenicity of 2-Bromopropane in the Sprague-Dawley rat

김종춘,오기석,신동호,김성호,김현영,윤효인,강성철,허정두,정문구,Kim, Jong-Choon,Oh, Ki-Seok,Shin, Dong-Ho,Kim, Sung-Ho,Kim, Hyeon-Yeong,Yun, Hyo-In,Jiang, Cheng-Zhe,Heo, Jeong-Doo,Chung, Moon-Koo The Korean Society of Veterinary Science 2003 大韓獸醫學會誌 Vol.43 No.4

The present study was undertaken to evaluate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure during the gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered subcutaneously to pregnant rats at dose levels of 0, 375, 750 and 1250 mg/kg/day. During the test period, clinical signs, mortality, body weights and food consumption were examined. All dams were subjected to caesarean section on GD 20 and their fetuses were examined for external, visceral and skeletal abnormalities. At above 750 mg/kg, toxic effects including signs of toxicity, suppressed body weight, decreased gravid uterine weight and reduced food intake were observed in pregnant dams. An increase in the fetal deaths, a decrease in the litter size, a reduction in the fetal body weight and an increase in the incidence of fetal morphological alterations were also found. There were no adverse effects on either pregnant dams or embryo-fetal development at a dose level of 375 mg/kg. These results suggest that a 14-day subcutaneous dose of 2-BP is embryolethal and teratogenic at above 750 mg/kg/day in pregnant rats. In the present experimental condition, the no-observed-adverse-effect level of 2-BP is considered to be 375 mg/kg/day for dams and embryo-fetuses, respectively.

Evaluation of the testicular toxicity caused by 2-bromopropane in rats

김종춘,이현숙,윤효인,정문구,Kim, Jong-choon,Lee, Hyun-sook,Yun, Hyo-in,Chung, Moon-koo The Korean Society of Veterinary Science 2000 大韓獸醫學會誌 Vol.40 No.2

최근 2-bromopropane(2-BP)이 사람과 실험동물에서 정소독성을 유발한다고 보고된 바 있다. 그러나 수컷 생식기계에 있어서 2-BP의 지연효과에 대해서는 세부적으로 조사된 바가 없다. 본 연구는 Sprague-Dawley 랫드에서 2-BP의 정소독성과 정자발생의 회복을 조사하기 위하여 수행하였다. 5주령의 수컷 랫드에게 2-BP를 1,000mg/kg 용량으로 4주간 반복투여하였고, 투여시작후 1, 2, 3, 4 및 12주째에 부검하였다. 정소독성의 평가는 병리조직학적인 질적평가와 생식기관 중량, 정자두부수 및 재생지수 등의 양적평가로 수행하였다. 시험결과 2-BP를 투여한 랫드에서는 체중과 정소 및 정소상체 중량이 대조군에 비해 시간의존적인 방식으로 억제 또는 감소하였다. 병리조직검사에서는 투여 1주째에 stage I~IV에서 정조세포와 stage VII~IX에서 세사전기 및 세사기의 정모세포가 현저하게 소실되었다. 정조세포는 투여 2주째에 모든 stage에서 광범위하게 소실되었으며, 정자발생주기가 진행됨에 따라 2, 3 및 4주째에는 접합기 정모세포, 비후기 정모세포 및 원형 정자세포가 전구세포의 결손에 의해 점진적으로 소실되었다. 지지세포의 기능적 이상을 암시하는 지지세포의 공포화와 정자세포 저류는 상기한 모든 시기에서 관찰되었다. 8주 회복후인 12주째에는 대부분의 곡세정관이 심하게 위축되어 지지세포만 관찰되었으며, 간질조직에서는 간질세포의 과형성이 인정되었다. 또한 2-BP에 의해 유발된 정소의 손상이 비가역적임을 암시해주는 정자두부와 재생지수의 현저한 감소가 관찰되었다. 상기결과는 랫드의 2-BP를 1,000mg/kg의 용량으로 4주간 반복투여하면 정조세포의 결손에 의해 점진적으로 생식세포가 감소하고 이로 인하여 장기적인 정소위축이 유발된다는 것을 암시해준다. It has been recently reported that 2-bromopropane (2-BP) induces male reproductive toxicity in both human and experimental animals. However, delayed effects of 2-BP on male reproductive system have not been investigated in detail. The present study was conducted to investigate the testicular toxicity of 2-BP and to determine the recovery of normal spermatogenesis in Sprague-Dawley rats. Male rats aged 5 weeks were administered 1,000mg/kg 2-BP by gavage daily for 4 weeks and sacrificed sequentially at 1, 2, 3, 4 and 12 weeks after initiation of 2-BP treatment. Testicular toxicity was evaluated qualitatively by histopathological examinations and quantitatively by reproductive organ weights, spermatid head count, and repopulation index. In the 2-BP treated rats, the body weights was significantly suppressed and the weights of testes and epididymides were also decreased in a time-dependent manner. On histopathological examination, spermatogonia in stages I-VI and preleptotene and leptotene spermatocytes in stages VII-IX were strongly depleted at 1 week of dosing. Spermatogonia were depleted extensively in all spermatogenic stages at 2 weeks. Continuing with the evolution of spermatogenic cycle, zygotene spermatocytes, pachytene spermatocytes, and round spermatids were sequentially depleted at 2, 3, and 4 weeks of dosing due to the depletion of their precursor cells. Vacuolization of Sertoli cells and spermatid retention were also observed at all time points, suggesting that 2-BP induced Sertoli cell dysfunction. At 12 weeks, after 8 weeks recovery, most of the tubules appeared severely atrophic and were lined by Sertoli cells only. Leydig cell hyperplasia in the interstitial tissue was also found. In addition, dramatic reductions in the number of spermatid heads and repopulation index were observed, indicating that 2-BP-induced testicular injury is irreversible. These results indicate that 4 weeks repeated-dose of 1,000mg/kg 2-BP results in a progressive germ cell loss due to the depletion of spermatogonia followed by long-term testicular atrophy in SD rats.

Single dose toxicity study of CKD-602, a new camptothecin anticancer agent, in Beagle dogs

김종춘,신동호,박승춘,손우찬,차신우,한정희,배주현,서정은,정문구,Kim, Jong-Choon,Shin, Dong-Ho,Park, Seung-Chun,Son, Woo-Chan,Cha, Shin-Woo,Han, Junghee,Bae, Joo-Hyun,Suh, Jeong-Eun,Chung, Moon-Koo The Korean Society of Veterinary Science 2004 大韓獸醫學會誌 Vol.44 No.1

The present study was carried out to investigate the potential acute toxicity of CKD-602 by a single intravenous dose in Beagle dogs. The test chemical was administered intravenously to male and female Beagle dogs at dose levels of 0.3, 0.5, or 2.5 mg/kg. Mortalities, clinical findings, and body weight changes were monitored for the 14-day period following the administration. At the end of 14-day observation period, all animals were sacrificed and complete gross postmortem examinations were performed. All males and females of the 2.5 mg/kg dose group were found dead between the fourth and seventh day after the injection. Treatment related clinical signs, including vomiting, anorexia, mucous stool, diarrhea, and no stool were observed. Decrease or suppression of body weight was observed in a dose-dependent manner. In autopsy, dark red discoloration of the gastrointestinal tract, atrophy of the thymus, paleness of the spleen, sporadic dark red spots of the lung and petechia of the heart were observed in dead animals of the 2.5 mg/kg dose group. There were no specific adverse effects on males and females of the 0.3 and 0.5 mg/kg dose groups, except for the transient clinical signs such as anorexia, vomiting, and mucus/no stool. On the basis of the results, it was concluded that a single intravenous injection of CKD-602 to Beagle dogs resulted in increased incidence of abnormal clinical signs and death, decreased body weight, and increased incidence of abnormal gross findings. The absolute toxic dose of this chemical was 2.5 mg/kg for both genders. The $LD_{50}$ value was 1.1 mg/kg (95% confidence limit not specified) for both genders. The no-observed-effect level (NOEL) was considered to be below 0.3 mg/kg for both genders.

랫드에 있어서 배양배자에 대한 Phenytoin의 최기형성 효과

김종춘,임광현,정문구,노정구,Kim, Jong-Choon,Lim, Kwang-Hyeon,Chung, Moon-Koo,Roh, Jung-Koo 한국독성학회 1998 Toxicological Research Vol.14 No.3

The teratogenic potential of the anticonvulsant drug phenytoin (PHT) has been well documented both in the human and in the experimental animals. However there are few reports on the effects of PHT on embryonic development in rats in vitro. The present study was performed to evaluate the teratogenic effects of PHT using whole-embryo culture system in rats. Sprague-Dawley rat embryos were explanted on gestational day (GD) 9.5 and cultured for 48 hrs in the immediately centrifuged and heat-inactivated rat serum containing 0,25,50, or $100{\mu}g$ PHT/mL. At the end of culture period the embryos were scored for morphological development according to the procedure of Van Maele-Fabry, and their total protein contents were determined. At 100 ${\mu}$g/mL of culture medium. PHT caused significant reduction in developmental score and protein content of embryos and a high incidence morphological abnormalities (100%). Characteristic malformations included altered yolk and embryonic circulation, craniofacial hypoplasia, neural tube schisis, branchial arch defects, abnormal ratation, and limb bud hypoplasia, among others. There were no adverse effects on embryonic growth and development at concentrations of 25 and 50 ${\mu}$g /mL of culture medium. The results indicated that the dysmorphogenic effect of PHT on cultured embryos is due to a direct interference with embryonic development.

비글견에 있어서 새로운 안트라싸이클린계 항암제 DA-125의 정소독성연구

김종춘,차신우,송시환,정문구,Kim, Jong-choon,Cha, Shin-woo,Song, Si-whan,Chung, Moon-koo 대한수의학회 1997 大韓獸醫學會誌 Vol.37 No.2

To assess the testicular toxicity induced by DA-125, a new anthracycline anticancer agent, the test substance was intraveneously administered to male beagle dogs at dose levels of 0, 0.0023, 0.0375, 0.15, and 0.6 mg/kg/day, 6 days a week for 26 weeks. At 0.6 mg/kg/day, 1 out of 3 dogs had died on day 42 of treatment and the other dogs were sacrificed on days 46 and 122 of treatment due to the increasingly severe clinical condition. Clinical signs considered to be related to treatment were included anorexia, vomiting, salivation, decreased activity, mucous and/or dark faeces, diarrhea, and swelling, abscess and/or ulceration of injection sites. Suppression in body weight gain, reduction in food intake, decreases in testicular weight and size, and hemorrhage of epididymis were also observed in male dogs. Microscopically, severe degenerative changes such as atrophy of seminiferous tubules, loss of germ cells, degeneration of germ cells, vacuolization of Sertoli cells, and hyperplasia of Leydig cells were observed in all dogs. Azoospermia in epididymal tubules, atrophy of epithelia in the cauda epididymis, and prostate atrophy were also found. At 0.15 mg/kg/day, anorexia, vomiting, salivation, diarrhea, and swelling of injection sites were observed. In addition, suppression in body weight gain and decreases in testicular weight and size were found in male dogs. Atrophy of seminiferous tubules, decrease of germ cells, degeneration, exfoliation and retention of germ cells, vacuolization of Sertoli cells, and hyperplasia of Leydig cells were observed by histopathological examination. Azoospermia in epididymal tubules and prostate atrophy were also found. At 0.0375 mg/kg/day, there were no clinical signs considered to be indicative of a reaction to treatment, but testicular size was significantly reduced. Microscopically, decreases in the number of spermatogonia and epidydimal speramtozoa were found. There were no evidences of general or testicular toxicity at 0.0023 mg/kg/day. These results indicate that DA-125 produces significant and persistent damage to the spermatogenic compartments of the testes in male beagle dogs.

수도권 지역 운행 경유차량내 후처리장치 적용 현황

김종춘(Jong Choon Kim),권상일(Sang Il Kwon) 한국자동차공학회 2008 오토저널 Vol.30 No.1

새로운 백금착물 항암제 SKI 2053R 의 토끼 최기형성시험

김종춘(Jong Choon Kim),김갑호(Kap Ho Kim),박종일(Jong Il Park),김형진(Hyoung Chin Kim),정문구(Moon Koo Chung) 한국응용약물학회 1999 Biomolecules & Therapeutics(구 응용약물학회지) Vol.7 No.3

SKI 2053R, cis-Malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II), is a newly developed antitumor platinum complex derived from cisplatin. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than cisplatin. Effects of test agent on general toxicity of does and embryonic development of F1 fetuses were investigated in rabbits. Sixty eight New Zealand white rabbits were distributed among three treated groups and a control group. SKI 2053R was administered intravenously to pregnant rabbits from days 6 to 18 of gestation at dose levels of 0, 0.67, 2.0, or 6.0 ㎎/㎏/day. The pregnant does were subjected to the caesarean section on day 28 of gestation. No treatment-related changes in clinical signs, body weight, food consumption, and necropsy findings were observed in all groups. F1 fetuses showed no changes related to the treatment of SKI 2053R, except that an increase in the incidence of skeletal variations were observed at 6.0 ㎎/㎏. There were no signs of maternal toxicity or embryotoxicity at 0.67 and 2.0 ㎎/㎏. The results show that the administration of 6.0 ㎎/㎏ SKI 2053R induces skeletal variations in fetuses and that the no observed adverse effect levels(NOAELs) of SKI 2053R are considered to be over 6.0 ㎎/㎏ for does and 2.0 ㎎/㎏ for F1 fetuses in rabbits.

실험동물의 발생이상 용어집

김종춘(Jong-Choon Kim),양영수(Young-Su Yang),안태환(Tai-Hwan Ahn),김성호(Sung-Ho Kim),정수연(Soo-Youn Chung),이규식(Gyu-Seek Rhee),정나영(Na-Young Chung),정문구(Moon-Koo Chung) 한국독성학회 2006 Toxicological Research Vol.22 No.3

This paper presents the first version of a Korean glossary of terms for structural developmental abnormalities in common laboratory animals, mainly rats, mice and rabbits. This is a translation of the glossary entitled Terminology and Developmental Abnormalities in Common Laboratory Mammals that was edited by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology. The purpose of the Korean glossary is to provide a common vocabulary that will reduce confusion and ambiguity in the description of developmental effects, particularly in submissions to regulatory agencies worldwide. The glossary contains a primary term or phrase, a definition of the abnormality, and notes, where appropriate. Selected synonyms or related terms, which reflect a similar or closely related concept, are noted. Non-preferred terms are indicated where their usage may be incorrect. Modifying terms used repeatedly in the glossary (e.g., absent, branched) are listed in Appendix A, and syndrome names are generally excluded from the glossary, but are listed separately in Appendix B. The glossary is organized into broad sections for external, visceral, and skeletal observations, then subdivided into regions, structures, or organs in a general overall head to tail sequence. Numbering is sequential, and not in any regional or hierarchical order. Uses and misuses of the glossary are discussed. Updates of the Korean glossary are planned based on the comments received.

랫드 전배아배양법을 이용한 2-Bromopropane의 최기형성 평가

김종춘(Jong-Choon Kim),신동호(Dong-Ho Shin),김성호(Sung-Ho Kim),양영수(Young-Soo Yang),오기석(Ki-Seok Oh),강성철(Cheng-Zhe Jiang),정문구(Moon-Koo Chung) 한국독성학회 2006 Toxicological Research Vol.22 No.2

Recently, we have reported that the environmental pollutant 2-bromopropane (2-BP) induces a significant embryo-fetal developmental toxicity in rats. However, the cause of deveopmental toxicity and the relationship between maternal and developmental toxicities could not be elucidated because the developmental toxicity of 2-BP was observed only in the presence of maternal toxicity. The in vitro teratogenicity study using whole embryo culture was carried out to understand the teratogenic properties and the possible mechanism of teratogenicity induced by 2-BP in rats. Rat embryos aged 9.5 days were cultured in vitro for 48 hrs at medium concentrations of 0, 1, 3, or 10 ㎎/㎖ of 2-BP. Embryos were evaluated for growth, differentiation, and morphological alterations at the end of the culture period. At 10 ㎎/㎖, 2-BP caused a delay in the growth and differentiation of embryos and an increase in the incidence of morphological alterations, including altered yolk sac circulation, abnormal axial rotation, craniofacial hypoplasia, open neuropore, absent optic vesicle and kinked somites. At 3 ㎎/㎖, only a delay in the growth and differentiation of embryos was observed. There were no adverse effects on embryonic growth and development at the concentration of 1 ㎎/㎖. The results showed that the exposure of 2-BP to rat embryos results in a developmental delay and morphological alterations at dose levels of 3 ㎎/㎖ culture media or higher and that 2-BP can induce a direct developmental toxicity in rat embryos.

랫드에서 이황화메틸의 2주 반복투여 흡입독성연구

김종춘(Jong-Choon Kim),신진영(Jin-Young Shin),신동호(Dong-Ho Shin),김성호(Sung-Ho Kim),이성배(Sung-Bae Lee),한정희(Jung-Hee Han),정용현(Yong-Hyun Chung),김현영(Hyeon-Yeung Kim),박승춘(Seung-Chun Park) 한국독성학회 2004 Toxicological Research Vol.20 No.3

The present study was carried out to investigate the potential toxicity of dimethyl disulfide<br/> by a 2-week inhalation in F344 rats. The test article, dimethyl disulfide, was exposed by inhalation<br/> to male and female rats at dose levels of 0, 33, 100, or 300 ppm/6 hrs/day for 2 weeks. At the<br/> end of treatment period, all males and females were sacrificed. During the test period, clinical signs,<br/> mortality, body weights, food consumption, hematology, serum biochemistry, and gross findings were<br/> examined. The mean body weights of the male 300 ppm group and the female 33 ppm or higher<br/> dose groups were significantly lower than those of the control group, respectively. The mean food<br/> consumption at male 300 ppm and female 100 and 300 ppm were significantly decreased compared<br/> with the controls. Some treatment-related serum biochemical changes, including decreased alkaline<br/> phosphatase at male 300 ppm and female 100 and 300 ppm, reduced total bilirubin at male 300<br/> ppm, and decreased alanine aminotransferase at female 300 ppm, were observed in a dose-dependent<br/> manner, but these findings were considered to be of no toxicological significance. There were no<br/> adverse effects on mortality, clinical signs, hematology, and necropsy findings in any treatment group.<br/> Based on these results, it was concluded that the 2-week repeated dose of dimethyl disulfide by inhalation<br/> resulted in suppressed body weight gain and decreased food consumption at the dose of male<br/> 300 ppm and suppressed or reduced body weight gain and decreased food consumption at the dose<br/> of female 33 ppm or higher. In the present experimental conditions, the no-observed-adverse-effect<br/> level (NOAEL) was considered to be 100 ppm/6 hrs/day for male rats and below 33 ppm/6 hrs/day<br/> for female rats.