Historical control data on prenatal developmental toxicity studies in rabbits.

Historical control data on rabbit prenatal developmental toxicity studies, performed between 1994-2010, were obtained from 20 laboratories, including 11 pharmaceutical and chemical companies and nine contract laboratories, in Japan. In this paper, data were incorporated from a laboratory if the information was based on 10 studies or more. Japanese White rabbits and New Zealand White rabbits were used for prenatal developmental toxicity studies. The data included maternal reproductive findings at terminal cesarean sections and fetal findings including spontaneous incidences of morphological alterations. No noticeable differences between strains or laboratories were observed in the maternal reproductive and fetal developmental data. The inter-laboratory variations in the incidences of fetal external, visceral, and skeletal alterations seem to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, and terminology of fetal alterations.

Gastric hairballs in rabbits: significance in developmental toxicity study.

We surveyed 1053 pregnant rabbits of the Kbl:NZW strain collected from 27 developmental toxicity studies to reveal the prevalence and significance of gastric hairballs. The incidence of hairballs was 2/525 (0.4%) in the control group and 17/528 (3.2%) in the high dose group. In the high dose group, 16 dams resulted in abortion or death. In addition, decreases in body weight and food consumption were more severe in dams with hairballs than in their group-mates without hairballs.

Effects of restricted feeding on fetal and placental development in pregnant rabbits.

In our previous study on the effects of restricted feeding on pregnant rabbits (Matsuoka et al., 2009), animals given 20 g/day of diet on and after gestation day 6 (GD 6) showed significant changes in blood coagulation-related parameters suggesting a tendency to bleed and a decrease in serum concentration of progesterone, an important factor to maintain pregnancy, on GD 22, and a half of them showed serum progesterone concentrations less than 4.0 ng/ml which resulted in abortions on and after GD 23. In the present study, the effects of restricted feeding of 20 g/day from GD 6 to GD 22 on embryo-fetal and placental development on GD 23 as well as on blood coagulation-related parameters and serum progesterone concentrations on GD 22 were examined in pregnant rabbits. As compared with the non-restricted feeding (Not-treated, NT) group, the restricted feeding (RF) group showed lower values of platelets, fibrinogen, activated partial thromboplastin time (APTT) and antithrombin III (ATIII) and a longer prothrombin time (PT), reflecting an inhibition of blood coagulation, and a decrease in serum progesterone concentration on GD 22. Cesarean section performed on GD 23 revealed that the RF group showed a tendency towards an increase in the embryo-fetal death index and lower body weights and placental volumes compared with the NT group. Histological examination of the placenta in the RF group revealed that the labyrinth zone was thin and many glycogen-containing cells still remained in the basal zone, suggesting a delay in placental growth.

Changes in blood parameters in pregnant Japanese White rabbits.

Changes in blood parameters, especially those related to blood coagulations, were examined on gestational days (GDs) 6, 18 and 28 in Japanese White rabbits. As compared with the non-pregnant group, the following changes were observed in the pregnant group. For blood coagulation-related parameters, fibrinogen, platelets and antithrombin time III (ATIII) was significantly increased on GD 18 and/or GD 28, and activated partial thromboplastin time (APTT) was significantly prolonged on GDs 18 and 28. For the other hematological and blood chemical parameters, hemoglobin and hematocrit values were significantly decreased on GDs 18 and 28. Reticulocyte counts significantly and prominently increased on GD 18 and then decreased to significantly lower levels than those in the non-pregnant group on GD 28. Eosinophils and basophil showed significant decreases on GD 18 and/or GD 28. The serum progesterone concentration reached its highest level on GD 18. Total protein (TP), albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), cholesterol, calcium, glucose and blood urea nitrogen were significantly decreased on GD 18 and/or GD 28. These results were almost similar to those in the pregnant New Zealand White rabbits (Mizoguchi et al., 2010).

Changes in blood parameters in New Zealand White rabbits during pregnancy.

Changes in clinical pathology parameters, particularly those related to blood coagulation, were examined throughout the gestation period in New Zealand White rabbits. As compared with the non-pregnant group, the following major changes were observed in the pregnant group. For blood coagulation-related parameters, platelets increased progressively and fibrinogen increased slightly from organogenesis, prothrombin time was significantly prolonged during organogenesis and shortened in the late fetal growth stage, activated partial thromboplastin time was significantly prolonged during the fetal growth stage, and antithrombin III increased during and after late organogenesis. Such changes in blood coagulation-related parameters during the later stages of gestation seem to be physiological responses in preparation for protecting against excessive haemorrhage or haemostasis at parturition. For the other haematological and blood chemical parameters as well as progesterone, red blood cell counts, haemoglobin and haematocrit began to decrease during organogenesis and continued to decrease thereafter. Reticulocyte counts significantly increased during organogenesis and decreased thereafter. White blood cell parameters, except for neutrophils, showed significant decreases during the fetal growth stage. Serum progesterone concentration reached its highest level early in organogenesis and decreased thereafter. Total protein, albumin, glucose, cholesterol, calcium, blood urea nitrogen and creatinine decreased significantly during the middle and/or late periods of gestation. In conclusion, the data obtained from the present study can be used as background data for effective evaluation of reproductive toxicology in rabbits, and pregnant rabbits may serve as models of pregnant women in research pertaining to clinical pathology and gestation.

Effects of restricted feeding on blood parameters in pregnant rabbits.

The effects of restricted feeding (20 g/day from gestational day (GD) 6 to 28) on pregnancy outcome and blood parameters were examined in pregnant rabbits. As compared with the group which was allowed free access to diet throughout the gestational period (NT group), the group subjected to restricted feeding (R group) showed significantly lower values in many parameters such as total protein, albumin and triglyceride on GDs 22 and 28, reflecting low nutritive conditions. In addition, there were significant changes in blood coagulation-related parameters, suggesting an imbalance between coagulation and anti-coagulation factors. Moreover, abortions occurred in about half of the animals of the R group between GDs 23 and 27. When aborted rabbits were compared with those which could maintain pregnancy under restricted feeding, total protein, albumin, platelets and antithrombin III values and especially blood progesterone concentration were significantly lower in aborted rabbits on GD 22, prior to occurrence of abortion. These results suggested that abortions due to restricted feeding might be brought about by lower nutritive conditions, an imbalance of blood coagulation-related factors and lower blood progesterone concentrations.

Characteristics of Kbl:Dutch rabbits in prenatal development in comparison with Kbl:New Zealand white rabbits.

Prenatal development of Kbl:Dutch rabbits was studied in comparison with Kbl:New Zealand white rabbits. Significantly accelerated ossification of the 5th and 6th sternebrae and a low incidence of fetuses with a 13th rib were characteristic features in the prenatal development of Kbl:Dutch rabbits in comparison with Kbl:New Zealand white rabbits. These characteristics were largely consistent with earlier studies of Dutch rabbits from different suppliers and are notable when Kbl:Dutch rabbits are used for the evaluation of skeletal ossification.

An investigation on restraining effects and acclimation to protecting jackets in pregnant rabbits -wearing from pre-mating through fetal organogenesis-.

The purpose of the present investigation is to evaluate the restraining effects of protecting jackets attached from the pre-mating period and thereafter up to completion of the fetal organogenesis in rabbits. Forty (40) Kbl:NZW mated rabbits 6 to 10 months of age were divided into 2 groups of 20 animals each. Animals in the treatment group (hereinafter referred to as JK group) were dressed in protecting jackets from Day -9 prior to mating (hereinafter referred to as GD -9) to GD 19 and another group of animals without protecting jackets was used as a control. The major restraining effects noted were decreases in body weight gain and food consumption, which were marked in the first 9 days of jacket-attachment during the pre-mating period. The decrease in body weight was still apparent over the whole gestation period. However, the mean body weight of the JK group finally reached the baseline level of the study at around GD 11. These findings demonstrated that the restraining effects in the present study persisted longer than those in the previous study, in which protecting jackets were used from GD 0 to GD 19 or GD 6 to GD 19. The fertility function and cesarean section findings were comparable to those in the control group. It may be concluded that the use of protecting jackets from GD -9 to GD 19 induced more prolonged effects on body weight loss than in previous findings where the jackets were attached from GD 0 to GD 19 or GD 6 to GD 19 and the time of starting the acclimation with the jackets appears to play a great role in reducing body weight loss.

Effects of stage and degree of restricted feeding on pregnancy outcome in rabbits.

This study's aim is to investigate the relationship between stage and degree of restricted feeding during the gestation period and occurrence of abortion, premature birth or fetal damage in rabbits. The study was composed of 5 groups of pregnant Kbl:NZW rabbits that consisted of 8 animals each. These groups were subjected to restricted feeding in the following ways: (A) control group, free access to food, (B) 60 g per day from gestational days (GD) 6 to 18 (middle period), (C) 20 g per day from GD 6 to 18, (D) 20 g per day from GD 19 to 28 (post-middle period), and (E) 20 g per day from GD 6 to 28 (middle and post-middle periods). Even though all dams in Groups A, B and C went to full term, abortion or premature birth occurred to 2/8 and 8/8 dams in Groups D and E, respectively. Fetal lethality increased in Group C, which was subjected to restricted feeding at 20 g/head/day in the middle period. Slight inhibition of fetal growth was recorded only in Group D, which was subjected to restricted feeding in the post-middle period. Restricted feeding at 20 g/head/day in the middle period induced no abortion or premature birth, but increased fetal lethality that in the middle and post-middle periods resulted in abortion or premature birth of all dams, and that in the post-middle period resulted in abortion or premature birth at low incidence and slightly inhibited fetal growth. These results demonstrated that the post-middle period is vulnerable to effects of reduced food consumption in pregnant rabbits.

Restraining effects of and habituation to protecting jackets in pregnant rabbits.

The present study was undertaken to elucidate restraint effects of protecting jackets that are used to protect against biting the sites of percutaneous application in pregnant rabbits. Animals wore protecting jackets from gestational Day (GD) 0 to 19 (GD 0 group) or from GD 6 to 19 (GD 6 group). Major restraint effects were decreases in body weight gain and food consumption, which were marked during the first 2 to 13 days in jackets, and diminished thereafter. Therefore, the animals in the GD 0 group had almost recovered from the effects on GD 16, but those in the GD 6 group were still under the effects of restraint on GD 19. The above findings indicate that early start of habituation to protection jackets will provide better results in practical reproduction studies using percutaneous application in rabbits.

Lack of inhibitory effects of green tea catechins in 1,2-dimetylhydrazine-induced rat intestinal carcinogenesis model: comparison of the different formulations, administration routes and doses.

Differences in the modifying effects of green tea catechins (GTC) on intestinal carcinogenesis by different formulations, doses and administration routes were investigated in male rats pretreated with 1,2-dimethylhydrazine (DMH). One hundred and eighty nine F344 male rats received subcutaneous injections of DMH at 40 mg/kg body weight twice a week for 3 weeks. Three days after completion of the carcinogen treatment, they were divided into nine groups. Each was administered a different source of 0.1% or 0.01% of GTC (Mitsui Norin Co. (M) or Taiyo Kagaku Co. (T)) either in the diet (D) or the drinking water (W), or basal diet and tap water alone without GTC for 33 weeks and then killed for autopsy. The survival rate tended to be lower with 0.01% MGTC (W) group than in the other groups. In the large intestine, although the multiplicity and/or incidences of adenomas showed tendencies for dose-dependent decrease in all GTC groups, and the average volumes of tumors tended to be decrease dose-dependently in the MGTC (W) and TGTC (W) groups, the multiplicity of carcinomas did not show such a trend, rather being significantly increased in the 0.01% MGTC (D) and 0.1% TGTC (W) groups. In the small intestine, the incidence and the multiplicity of tumors in all GTC treated groups had a tendency to decrease. On the other hand, the volume of tumors was increased with statistical significance in the 0.01% MGTC (W) and 0.1% TGTC (W) groups. Thus it can be concluded that GTC does not exert chemopreventive effects on intestinal carcinogenesis irrespective of its formulation, dose or route of administration.