Optimal levels of nitric oxide are crucial for implantation in mice

This study was performed to clarify the critical role of optimal levels of nitric oxide on fecundity in mice during the implantation period. Mature female pregnant mice were treated with either nitric oxide donor molsidomine (3, 15, 60 mg kg(-1)) or nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-name; 0.3, 1.5, 6 mg kg(-1)) every 12 h, seven times from the night of Day 2 to Day 5 of gestation. They were killed on Day 14 of gestation. Pregnancy rates in each group (n = 22) and the number of live or absorbed fetuses in each mouse was calculated. The pregnancy rates in the experimental group were reduced in a dose-dependent manner. The rate in the control group was 100%, whereas those in the 60-mg molsidomine and 6-mg L-name groups were 40.9 and 31.8%, respectively. Histological analysis of uteri on Day 5 of gestation after treatment with 60 mg molsidomine or 6 mg L-name suggested retarded decidualization of stromal cells or defective function of predecidualized cells. In conclusion, optimal levels of nitric oxide are crucial for endometrial function and embryo implantation.     

孕期二月桂酸二丁基锡暴露对大鼠妊娠结局及胎鼠性发育的影响

目的 研究二月桂酸二丁基锡(DBTD)暴露对Wistar大鼠妊娠结果的影响并评估其对胎鼠性发育的影响.方法 在妊娠第12～19天分别用玉米油和不同浓度的DBTD(10、20、30 mg/kg)灌胃染毒孕鼠,至妊娠第20天,检测母鼠妊娠结局.结果 妊娠20 d时,孕鼠体重随DBTD剂量升高呈下降趋势,但与对照组比较,差异无统计学意义,30 mg/kg组孕鼠子宫重量显著降低;所有DBTD染毒组雄性、雌性胎鼠体重均显著降低,20、30 mg/kg组胎鼠体长显著降低;所有DBTD染毒组雌性胎鼠肛门距生殖器的标化距离显著增长,而雄性胎鼠无显著变化.各DBTD暴露组均未导致胎鼠发生外部畸形,但导致胎鼠趾骨骨化延迟,且在20、30 mg/kg组出现死胎和吸收胎.结论 DBTD暴露影响胎鼠的发育,并可能对雌性胎鼠具有雌性雄性化影响.     

虎眼万年青的致畸试验研究

目的探讨虎眼万年青对大鼠的致畸作用。方法用大鼠进行致畸胎试验,将动物分成5组:阴性对照组(蒸馏水)、虎眼万年青低剂量组(2.5 g/kg)、中剂量组(3.3 g/kg)、高剂量组(4.1 g/kg)和阳性对照组(维生素A),分别在妊娠的7～16 d灌胃给予。妊娠期间记录孕鼠体重,于妊娠第20天断头处死孕鼠,记录着床数、活胎数、死胎数和吸收胎数;检查胎鼠外观、内脏和骨骼,并称胎鼠体重,量体长。结果阳性对照组,活胎率为90.7%,与对照组(99.3%)比较明显降低(P0.05);迟死胎率和吸收胎率分别为1.3%、7.9%,与对照组比较明显增高(P0.05)。4.1、3.3、2.5 g/kg剂量组的孕鼠和胎鼠的各项毒效应观察指标与对照组相比,差异均无统计学意义(P0.05)。结论在该实验剂量与条件下,虎眼万年青对孕鼠生长和胚胎发育无不良影响和致畸作用。     

Effect of chemical sympathectomy and adrenergic agonists on the fertility of mice.

These experiments were designed to determine whether the adrenergic nerves present in the mouse oviduct are required for normal fertility and whether alpha and beta adrenergic agonists could modify fertility. Female hybrid mice were placed with fertile males. The presence of a vaginal plug was considered Day 1 of pregnancy. From Days 1-5 the mice were given 1 of the following drugs injected intraperitoneally 2 times a day: oxymetazoline hydrochloride, methoxamine hydrochloride, salbutamol sulphate, or isoproterenol hydrochloride. Controls received only the diluent. All were sacrificed on Day 12 of pregnancy and the number of fetuses recorded. Another group of mice received 6-hydroxydopamine hydrobromide in .1 ml of diluent intraperitoneally daily in doses from 8 mg/kg on Day 1, 12 mg/kg on Day 2, 15 mg/kg on Day 3, and 40 or 60 mg/kg on Day 4. Mice were mated on Day 5 and sacrificed on Day 19 when fetuses were counted. To determine completeness of denervation other animals so treated were sacrificed on Day 7 and the ovaries and oviducts studied. An 80% reduction in uptake of tritiated metaraminol in oviducts and ovaries was shown while fluorescence microscopy indicated that the oviducts and ovaries were essentially completely adrenergically denervated. The 6-hydroxydopamine pretreatment did not affect the fertility of the mice. Denervation of peripheral tissue was only partial. Of the drugs tested (oxymetazoline, methoxamine, salbutamol, and isoproterenol) only oxymetazoline at the highest dose levels had any effect on fertility. It was concluded that the presence of a functional adrenergic innervation is not necessary for normal ovulation or ovum transport and that only the long-acting potent alpha agonist oxymetazoline affected mouse fertility.     

Role of corticosterone in cleft palate formation in methylmercuric chloride-treated mice

The effect of simultaneous administration of sodium selenite and methylmercuric chloride on plasma corticosterone, and the effect of adrenalectomy and methylmercuric chloride treatment on the incidence of fetal cleft palate in mice were examined. After 6 consecutive days of treatment, methylmercury (as methylmercuric chloride) at 5 mg/kg per day increased plasma corticosterone to approximately twice the concentration observed in the controls. When administered together, selenium (as sodium selenite) at 125–135 mg/kg per day did not affect the increase of plasma corticosterone induced by methylmercuric chloride. Selenite by itself (125–135 mg selenium/kg per day) resulted in an increase of approximately 50% over the controls. Sham operation or adrenalectomy of mice on Day 7 of pregnancy did not result in a significant incidence of cleft palate in the fetuses. However, the administration of methylmercury (5 mg/kg per day) on Days 11, 12, and 13 of gestation to the operated mothers resulted in cleft palate in approximately 30% of the fetuses, regardless of the type of operation. The significance of these findings is discussed.     

杭州湾南岸滩涂沉积物中POPs混合物对小鼠的生殖毒性作用

目的研究杭州湾南岸滩涂沉积物中POPs混合物对小鼠的生殖毒性作用. 方法选择健康清洁级性成熟ICR小鼠80只,体重22-26g,随机分为30,100,300mg/kg三个剂量染毒组和一个溶剂对照组,每组20只,雌雄各半,进行一代生殖毒性试验.采用灌胃方式进行染毒(10 ml/kg),雄鼠染毒6周,进行精子畸形测定.雌鼠染毒2周后,雌雄小鼠按1:1同笼交配,交配时间为2周,观察交配率及受孕率.孕鼠在妊娠19天解剖,观察黄体数,着床数,活胎数,死胎数,吸收胎数,每窝胎仔平均胎长,胎重,胎盘重.结果 当混合物染毒剂量为100 mg/kg和300mg/kg 时,精子畸形率明显升高(P<0.05),剂量达到300mg/kg时生育率,妊娠率,活胎率,平均胎长和胎仔重降低(P<0.05),而着床前死亡率,死胎率升高(P<0.05).结论 滩涂沉积物中POPs混合物在剂量达到300mg/kg时对小鼠产生明显的生殖和发育毒性.     

Effect of sodium selenite on methylmercury-induced cleft palate in the mouse

The effects of simultaneous administration of sodium selenite on the teratogenic action of methylmercury was examined. Methylmercury, or sodium selenite, or a mixture of methylmercury and sodium selenite was administered subcutaneously to pregnant ICR-strain mice on Days 9 through 12 or Days 7 through 12 of gestation, and intraperitoneally to pregnant C57BL-strain mice on Days 7 through 12 of gestation. On Day 17 of gestation the fetuses were removed and examined for cleft palates. Although the incidence of cleft palate in the fetuses, on Day 17, differed according to the concentration of methylmercury (3 or 5 mg/kg/day) and the duration of administration (1 injection per day for 4 or 6 days), the simultaneous administration of selenium at concentrations of 0.0625 to 3.5 mg/kg/day did not reduce the incidence of cleft palate. At the higher concentrations (0.5 to 3.5 mg/kg/day) selenium appeared to increase the maternal toxicity and the teratogenicity of methylmercury. Analysis of fetal body weights on Day 17 of gestation indicated that in those groups in which methylmercury alone resulted in a significant decrease in body weight, the simultaneous administration of selenium did not prevent this growth suppression. It is suggested that cleft palate induction by methylmercury is the result of suppression of growth, rather than a tissue-specific teratogenic action. The effects of methylmercury and selenium on other parameters of maternal and fetal health are also discussed.     

Effect of intrauterine copper wire on resorption of fetuses in rats

A copper ring was transfixed through the uterine lumen after implantation (Day 6 of pregnancy) in the rat. The copper ring was either left $\text{in situ}$ or removed during pregnancy. The incidence of resorption of embryo in relation to the duration of the copper present in the uterus was examined.In the first experiment, the percentage of the fetuses which were resorbed increased from 16.7 on Day 12 to 59.6 on Day 18 when the wire remained $\text{in situ}$. In the second experiment, only 15.4% of the fetuses were resorbed by Day 18 and Day 21, when the wire was removed on Day 12. However, 25.9% of the fetuses were resorbed on Day 18 and 48.1% on Day 21, when the wire was removed on Day 18.The results indicate that an intrauterine copper wire did affect the incidence of resorption of fetuses and that this effect upon the fetuses became apparent only after Day 12 of pregnancy.It can be concluded from this study that the longer the copper remains in the uterus during the late stages of pregnancy, the greater effect it has upon the rate of resorption of the fetuses.     

壬基酚和双酚A对小鼠生育力的联合作用

目的研究双酚A(bisphenol A,BPA)、壬基酚(nonylphenol,NP)对小鼠生育力影响的联合作用类型,为正确评价BPA,NP在环境中共存时对机体产生的损害效应提供毒理学依据。方法选择健康、性成熟、体重22-24 g清洁级昆明种小鼠400只,雌雄各半,随机分为BPA低、中、高剂量染毒组(48,120,240 mg/kg),NP低、中、高剂量染毒组(24,60,120 mg/kg)和(NP BPA)低、中、高剂量混合染毒组(NP 12 mg/kg BPA 24 mg/kg,NP 30 mg/kg BPA 60 mg/kg,NP 60 mg/kg BPA 120 mg/kg)。按美国FDA推荐方法进行生育力研究,并应用金正均法对混合染毒BPA和NP对生育力影响的联合作用进行评价。结果活精率、交配率、着床率在混合染毒的低、中剂量组中,其联合作用均为相加作用,在高剂量组为拮抗作用;妊娠率在低剂量组为相加作用,在中、高剂量组为拮抗作用,精子形态正常率在低、中、高各剂量组均为相加作用;生育力、活胎率、死胎率在低、中、高剂量组均为拮抗作用。结论BPA和NP对小鼠生育力影响的联合作用类型,在低剂量组为相加作用,在中剂量组既有相加作用,又有拮抗作用,在高剂量组主要为拮抗作用。     

The influence of a high-protein, low-carbohydrate diet on bone development in the fetuses of rat dams with streptozotocin-induced diabetes

1. The purpose of the present study was to determine the effects of diet on the mandibles and growth centres of the long bones in the fetuses of diabetic rat dams given a normal diet compared with those given a high-protein, low-carbohydrate diet. 2. On the 9th day of gestation, the controls, groups 1 and 3, were injected with citrate buffer and given 200 and 600 g protein/kg diets respectively. Groups 2 and 4 were injected with 40 mg streptozotocin/kg body-weight and pair-fed with groups 1 and 3 respectively on the 200 and 600 g protein/kg diets. 3. On day 22, some dams were injected with either 45Ca or [14C]proline. Mandibles and long bones were removed and weighed and analysed for Ca content, 45Ca uptake, collagen and collagen synthesis. 4. The body-weights, and mandibular and long-bone weights of the fetuses in the diabetic 200 g protein/kg group were smaller than those of the non-diabetic 200 g protein/kg group, whereas those of the diabetic 600 g protein/kg group showed no difference from the non-diabetic 600 g protein/kg group. 5. The rate of collagen synthesis was higher in the fetuses of the diabetic 600 g protein/kg group than those of the non-diabetic group. Bones of the diabetic 200 g protein/kg group were lower in collagen content when compared with the non-diabetic group, whereas there was no difference between the diabetic and non-diabetic 600 g protein/kg groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gestational protein-energy malnutrition affects the composition of developing skins of rat fetuses and their dams

1. Various biochemical variables of the skins of rat dams and their fetuses in which protein-energy malnutrition was induced during pregnancy were analysed. 2. One group of dams was fed on a 200 g protein/kg diet as a control and the other was fed on a 60 g protein/kg diet as an experimental group. Each group of dams was fed from day 13 of gestation until day 22. 3. Water, protein and hexosamine concentrations of the fetal skins in the malnourished group were greater than those in the control group, whereas in the dams' skins, protein concentration was greater in the malnourished group than in the control group. 4. Extractability of collagen with neutral salt and pepsin showed no difference between the groups in the skins of fetuses and dams. The content of type III collagen in the fetal skin did not differ between the groups, but was increased in the malnourished dams' skins compared with that of the control group. 5. The present study showed that protein-energy malnutrition during pregnancy significantly affects the metabolism of the skin in both fetuses and their dams. Furthermore, the skins of fetuses and dams are structurally altered in different ways by this nutritional stress.     

Intrauterine growth retardation is associated with reduced cell cycle activity, but not myofibre number, in ovine fetal muscle

Cellular development of muscle was studied in sheep fetuses at 85 days of gestation. Large and small fetuses were compared at 100, 115 and 130 days, and an additional group of large 130-day fetuses were studied following 7 days of maternal undernutrition. Myogenesis in the peroneus longus muscle was completed between 100 and 115 days of gestation, and myofibre number did not differ between small and large fetuses. The proportion of myofibre-related nuclei identified as entering S-phase of the cell cycle was 1.7% per hour in 85-day fetuses. In large fetuses, subsequent rates were relatively constant (approximately 1.5% h(-1)), whereas in small fetuses cell cycle activity declined with age from 1.3 to 0.9% h(-1), and was 0.5% h(-1) in 130-day fetuses of restricted ewes. The constant rate of cell cycle activity in large fetuses was associated with an increasing estimated rate of muscle growth (peroneus longus (mg) = 0.831 x 10(0.024 x age [d]), r2 = 0.98), which contrasted with slow and relatively constant muscle accretion in small fetuses (8.4 mg day(-1)), and slower muscle accretion at 130 days in large fetuses from restricted ewes. Differences in DNA and RNA content in the semimembranosus muscle increased with age, large fetuses having 70% more muscle DNA, 108% more muscle RNA and 104% larger muscles than small fetuses at 130 days (all P<0.001). The results demonstrate that myonuclei accumulation, but not myofibre number, is associated with fetal growth in sheep and, therefore, with fetal nutrition during mid to late gestation.     

叶酸和维生素B_(12)联合抗酒精发育毒性的实验研究

目的:研究叶酸(FA)和维生素B12(VB12)联合抗酒精发育毒性的效果。方法:以5g/kg乙醇灌胃孕D6～D15的ICR小鼠建立酒精发育毒性动物模型,于孕D1～D16每天按三个组别分别灌胃FA60mg/kgbw、VB121mg/kg、FA60mg/kgbw+VB121mg/kgbw,设酒精模型组和阴性对照组,所有动物于孕D18剖杀观察。结果:与酒精模型组比较,FA和VB12联合干预组孕期母鼠增重下降现象明显改善,活胎率显著增加,活胎体重、身长、尾长均显著增加,胸骨、枕骨、四肢骨骨化异常发生率显著下降(P<0.01),尾椎骨骨化点数显著增加(P<0.01);FA单独干预组上述发育毒性表现也有一定程度的改善,但不如联合组;VB12单独干预组的预防作用不明显。结论:FA和VB12联合干预对酒精的发育毒性具有预防控制作用。     

Abortifacient effect of Prangos ferulacia on pregnant rats

PURPOSE: Prangos ferulacea grows in southern Iran and used in Iranian herbal medicine for gastrointestinal disorders, but it seems it has an abortifacient effect on pregnant women. To verify its potential as an abortifacient agent, we administered the leaves of this plant to pregnant rats. MATERIAL AND METHODS: Hydroalcoholic and aqueous extract of the leaves was administered orally at different doses to 60 rats on the first 18 days of pregnancy. Group 1 (G1) was considered as control group and was given only water. Groups 2-5 (G2-G5) received 25, 50, 100 mg/g per day and Groups 6-8 (G6-G8) received 300, 500 and 1000 mg/g per day, respectively. On Day 18 of pregnancy, they were killed and laparotomized. The uterine horns of each group were opened to see whether they contained any live and degenerated/dead fetuses. We used Student's t-test to analyze the data (p < or = .05 was considered significant). RESULTS: Of the total 504 fetuses in the studied groups, 13 fetuses (2.57%) were aborted. The abortion rate in the control group was 2 (1.94%) of 103 fetuses; the abortion rate was higher in the treated groups but not statistically significant. There was no relationship between the dose and type of extract and abortion rate in all studied groups. CONCLUSION: This study shows that the aqueous or hydroalcoholic extract of P. ferulacea is ineffective on the rate of abortion of pregnant rats. Future studies should be performed with higher doses to test the efficacy of this agent on other animals.     

Hexachlorobenzene (HCB) deposition in maternal and fetal tissues of rat and mouse. I. Chemical quantification of HCB in tissues

CD-1 mice received a single treatment of hexachlorobenzene (HCB) on Day 11 or 16 of gestation or daily treatments on Days 6–11 or 6–16 of gestation at levels of 10, 50, or 100 mg/kg. CD rats received daily treatments of 10 or 50 mg/kg HCB on Days 6–12 or 12–16 of gestation. Animals were sacrificed 24 hr after last dose and maternal and fetal tissues were assayed for HCB content. Rat and mouse fetuses and placentas showed a dose-dependent concentration of HCB, and generally, the fetuses had a lower concentration than their respective placentas. Multiple low doses of HCB resulted in higher concentrations of HCB in mouse maternal and fetal tissues than single doses of equivalent total dose. Late gestational rats received fewer doses of HCB than midgestational rats, yet their fetuses and placentas had significantly higher concentrations of HCB suggesting a gestational effect. Resorptions had higher average HCB concentrations than their living counterparts at all dose regimens.     

佩尔地平对妊娠期高血压疾病降压效果的影响

目的:探讨佩尔地平治疗妊娠期高血压疾病的降压效果,及对妊娠结局的影响。方法:90例患者随机分为佩尔地平组、硝苯地平对照组各45例,治疗组给予佩尔地平(由日本山之内制药株式会社提供)2mg加入5%葡萄糖注射液20ml静脉缓慢推注,继以8～20mg加入5%葡萄糖注射液200ml以每分钟30～40μg的速度静脉滴注维持,根据血压调整滴速。对照组仅给予硫酸镁加硝苯地平缓释片20mg,2次/日开始,根据患者血压情况每3天增加1次剂量,最大至30mg,2次/日。观察比较两组24h后血压、心率、胎心率及对妊娠结局的影响。结果:两组治疗前收缩压、舒张压、心率水平比较差异无统计学意义(P0.05),治疗24h后,两组收缩压、舒张压水平均较治疗前下降,差异有统计学意义(P0.05);两组治疗前后心率、胎心率比较差异无统计学意义(P0.05)。治疗组平均维持妊娠时间比对照组显著延长(P0.05),且治疗组产后出血量明显少于对照组,但治疗组Apgar评分8分以上胎儿数显著高于对照组(P0.05)。结论:佩尔地平对妊娠期高血压疾病降压效果好,在迅速降压的同时能很好地控制降压的幅度,避免对胎儿造成不利影响,能达到延长孕周的目的,值得临床推广和应用。     

转乙肝抗原蛋白基因苜蓿胚胎毒性和致畸性研究

目的采用动物实验对转乙肝抗原蛋白基因苜蓿（ATHAPG）的大鼠胚胎毒性和致畸性进行研究,为探索ATHAPG对人体健康影响和制订每日允许摄入量提供依据。方法将受孕sD大鼠随机分为40、200和1000mg／kg3个剂量组及阴性对照组（蒸馏水）。每组12～14只孕鼠,于孕期7～16d每天给受试动物灌胃1次,妊娠第20天处死,检查孕鼠妊娠与胎鼠畸形情况。结果3个剂量组的孕鼠生殖能力、体熏及胎鼠体重、外观发育、骨骼和内脏畸形率与阴性对照组比较,差异均无统计学意义（P〉0．05）。结论在该试验条件下,ATHAPG在40～1000mg／kg剂量范围对大鼠无明显的母体毒性、胚胎毒性和致畸性。     

Effect of hypobaric hypoxia on lamb intrauterine growth: comparison between high- and low-altitude native ewes

The present studies assessed the effect of hypobaric hypoxia on fetal lamb growth in high-altitude (HA) and low-altitude (LA) native ewes. Growth patterns of fetal biparietal diameter (BPD), abdominal diameter (AD) and thorax height (TH) were described by consecutive ultrasound measurements throughout the entire pregnancy. Three groups of animals were used: (1) pregnant LA ewes kept at LA (control; 'LL' group); (2) pregnant LA ewes moved to HA immediately after confirmation of pregnancy ('LH' group); and (3) pregnant HA ewes kept at HA throughout the entire pregnancy ('HH' group). The slope of the BPD curve was higher in LL fetuses followed by that in LH fetuses. During the last month of pregnancy, TH was higher in LH and HH fetuses, whereas AD was higher in LL than in LH fetuses. The length of gestation was longer in HH ewes (153.2 +/- 4.3 days) than in LH and LL ewes (146.0 +/- 5.5 and 145.0 +/- 3.0 days, respectively). Bodyweight at birth was higher for LL newborns (4.2 +/- 0.3 kg) than for LH and HH newborns (3.0 +/- 0.5 and 3.2 +/- 0.8 kg, respectively), whereas placental weight was higher in the HH group (396 +/- 80 g) than in the LH (303 +/- 64 g) and LL (280 +/- 40 g) groups. In conclusion, an HA environment modifies fetal growth and pregnancy outcome with the magnitude of effects depending on the time of residence at HA.     

Maternal caffeine consumption during pregnancy does not affect preimplantation development but delays early postimplantation growth in rat embryos

Models for studying prenatal drug-induced intrauterine growth retardation (IUGR) have, without exception, measured growth-related factors in the postimplantation embryo, fetus or neonate. Therefore, it is not known whether effects of drug exposure on growth and metabolism begin early in the preimplantation embryo, or whether IUGR is exclusively a postimplantation phenomenon. The present study investigates whether caffeine, a drug known to induce a dose-dependent fetal IUGR, affects embryo development before and/or after implantation or is exclusively a fetal phenomenon. Preimplantation embryo assessment (with treatment from Days 2 to 4 of pregnancy) included glucose utilization, cell number evaluation and stage of development (morula to hatched blastocyst); whereas, postimplantation embryo assessment (treatment from Days 2 to 10, 10.5 or 11 of pregnancy) included somite number evaluation and extent of neural tube closure, as seen using scanning electron microscopy. Comparing control preimplantation embryos with those exposed to 30 and 60 mg kg(-1) caffeine did not reveal any effects of caffeine exposure, as assessed on Day 5 of gestation. However, postimplantation embryo development assessed on Day 12 of gestation revealed that caffeine exposure of 15 and 30 mg kg(-1) significantly reduced, at both dosage levels, somite number and the extent of neural tube closure. In addition, comparisons of control and experimental groups revealed that in the high-dose caffeine group the forebrain cavity was significantly enlarged and bounded by a reduced, irregularly aligned neuroepithelium. The findings suggest that IUGR is a phenomenon first identifiable during late postimplantation embryogenesis and continues in fetal life.     

Effect of the Day of Administration on the Developmental Toxicity of Tributyltin Chloride in Rats

The objective of this study was to determine the susceptible day for the teratogenicity of tributyltin chloride (TBTCI) by a single administration on one of the days during organogenesis. Pregnant rats were given a single dose of TBTCI by gastric intubation at 100 mg/kg on either day 7, day 8, or day 9 and at 200 mg/kg on either day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, or day 15 of pregnancy. The maternal body weight gain in the period immediately following administration in all TBTCI-treated groups was significantly decreased. A significant increase in the incidence of postimplantation loss was found after administration of TBTCI on day 7, day 8, and day 9 at 100 and 200 mg/kg and on day 10 and day 11 at 200 mg/kg. A significantly increased incidence of fetuses with external malformations was detected when TBTCI was given on day 8 at 100 and 200 mg/kg and on day 11, day 12, day 13, and day 14 at 200 mg/kg, and the most pronounced effect occurred after administration on day 13 of pregnancy. Cleft palate was observed exclusively after administration during late organogenesis. It could be concluded that the manifestation and susceptibility of the developmental toxicity of TBTCI vary with the developmental stages at the time of administration and that TBTCI has the biphasic sensitivity to teratogenicity on day 8 and days 11–14 of pregnancy. Received: 1 July 1996/Revised: 28 November 1996