ABSTRACT S1c:Wistar-KY rats were administered orally with 62.5, 125, 187.5 or 250 mg/kg aspirin suspended with 0.5 % CMC-Na on days 9-1 1 of gestation (plug t = day 0). Suppression of maternal weight gain and food consumption during treatment was observed at and over 187.5 mg/kg. At term, the fetal mortality increased at and over 187.5 mg/kg and the fetal weight was lowered at and over 125 mg/kg. Among 15 live fetuses at 250 mg/kg, 4 had external malformations. In the skeletal examination (double staining), skeletal anomalies increased at and over 187.5 mg/kg. The skeletal variations such as vertebral anomalies, fused costal cartilages and increased presacral vertebrae were often encountered and delayed ossification was also found at and over 125 mg/kg. The internal anomalies tended to increase at and over 187.5 mg/kg. The live birth rate was significantly lower at 187.5 mg/kg than that in controls, and all pups, except for 3 from a dam, died before weaning. At 125 mg/kg, the pivoting locomotion on day 7 post partum was poorer as compared with controls. The physical and functional development at 62.5 mg/kg was not changed. There were no significant effects on male off- spring in the open-field, rotarod, under-water T-maze and avoidance learning tests. However, in the Biel T-maze test (9-10 weeks of age), the aspirin-treated groups showed more errors and the increased elapsed time on the 1st trial day than controls. These results indicate that aspirin may induce a slight learning defect on rat offspring even at the non-teratogenic dose and the Biel T-maze test is more sensitive than any other learning tests given in this study.
ABSTRACT Nation-wide data in Japan between 1969-1982 on 3,650 cases of fetal death and 2,397 cases of postnatal death caused by congenital hydrocephalus were analyzed. The prevalence rate of congenital hydrocephalus decreased yearly. This reduction is attributed to prenatal detection and selective abortion among fetal deaths, and surgical correction of hydrocephalus postnatally. The prevalence rate per 1,000 .births was 0.22 in urban areas and 0.25 in rural areas between 1969- 1982, and the difference was significant. The prevalence rate was slightly higher in the southwest part of Japan than in the northeast. Social class variation in the prevalence rate was present.
ABSTRACT This study was designed to elucidate long-term pathological effects of ochratoxin A, one of the food contaminating mycotoxins, on the developing brain in mice. A single intraperitoneal injection of ochratoxin A at a dose of 2 or 3 mg/kg was given to pregnant mice on day 10 of gestation. They were allowed to give birth and the offspring were examined 6 weeks after birth. Their body weight, brain weight, brain size, thickness and cell packing density of dorsal neo- cortex in histological sections were examined. Growth of basal dendrites of pyramidal neurons in the layer V of dorsal neocortex was also examined with Golgi-Cox specimens in terms of number of dendrites directly arising from the perikaryon, number of endings of dendrites, branching index (No. of endings/No. of arisings), mean distance from the perikaryon to the tips of dendrites, and number of intersections of dendrites with the zonal boundaries. Significant changes were found in brain weight, anteroposterior length of cerebrum, mean distance from the perikaryon to the tips of dendrites and number of intersections of dendrites with the zonal boundaries. These parameters can be recommended as sensitive ones in order to estimate rather weak effects of cytotoxic chemical agents exposed in utero on the development of cerebral cortex.
ABSTRACT The testing of drugs and other chemicals in pregnant animals is required by legislation in a number of countries as a screening procedure for teratogenic potential in the human. The testing procedure involves methodology designed in the 1960s which was based on regimens established in the 1940s for toxicity testing. The requirement that animals are dosed to maternally toxic levels, frequently means that the embryos are exposed to inappropriately high concentrations of the test substance. Positive results in this type of experiment may have no relevence to the human situation where the exposure profile is often quite different, with the human embryo being exposed for prolonged periods to much lower drug concentrations. One way of duplicating the anticipated human exposure is to grow rat embryos in serum containing the drug and/or its metabolites at concentrations determined in the human during early clinical testing. It is proposed that mammalian embryos will respond in a similar manner to a particular concentration of a test substance. In vitro experiments using isotretinoin and its main metabolite 4-0x0-isotretinoin showed that the metabolite was teratogenic at concentrations which occurred in the human during normal repetitive dosing and hence the metabolite was the likely human teratogen. Similarly, rat embryo culture studies showed that the anticonvulsant drug, valproic acid, was teratogenic at blood concentrations which occurred during normal dosing in the human. Other in vitro studies showed that cadmium is unlikely to be a human teratogen, despite the fact that it is well established as a teratogen in experimental animals in vivo. It is proposed that embryo culture should be used as an adjunct procedure during teratology testing making use of metabolic and pharmacokinetic data obtained from the human during clinical testing.
ABSTRACT The effects of folic acid (FA) and folinic acid (FNA) on the tera-ｔogenicity of the antifolate drug pyrimethamine (PYR) were examined in rats. PYR and FA were orally administered with mashed feed. FNA was intraperitoneal- ly injected. The drugs were administered for 5 days of day 11-15 of gestation. Six groups were made; G-I PYR 1.6 (mg/kg/day), G-I1 PYR 3.6, G-111 PYR 1.6 + FA 50, G-IV PYR 3.6 + FNA 12, G-V FA 50, G-VI control. No malformations were found in G-I, IV, V and VI. All fetuses in G-I1 and 111 had malformations. Main malformations in G-I1 and 111 were cleft palate and brachygnathia. Accordingly it might be demonstrated that the teratogenicity of PYR was potentiated by concurrent FA in rats.