Cardiopathic effects of dichloroacetate in the fetal Long-Evans rat.

Dichloroacetic acid (DCA) is a by-product of the chlorine disinfection of water and may occur in treated water at levels exceeding 100 micrograms/L. Previous studies revealed teratogenic effects, particularly heart malformations, at high doses (900-2,400 mg/kg given on days 6-15 of pregnancy). In a series of three studies, groups of 7-10 Long-Evans rats were dosed with 1,900 mg/kg of DCA on days 6-8, 9-11, or 12-15; with 2,400 mg/kg on days 10, 11, 12, or 13; and with 3,500 mg/kg on days 9, 10, 11, 12, or 13, in an attempt to determine the most sensitive period and further characterize the heart defect. In a fourth study, six dams were treated with 1,900 mg/kg of DCA days 6-15 of pregnancy, and 56 fetuses were harvested for light microscopy of the heart. Eight control fetuses from four litters were also examined. No heart malformations were seen in the groups treated with 1,900 mg/kg DCA days 6-8 but were present in the group treated on days 9-11 and 12-15, with the higher incidence occurring on days 12-15. Single doses of 2,400 mg/kg DCA given on days 10, 11, 12, or 13 resulted in a much lower incidence of cardiac malformations, which occurred only on days 10 and 12. The high dose of DCA (3,500 mg/kg) did not increase the incidence of heart defects but showed that dosing on day 9 as well as on days 10 and 12 would produce the defect. The defects seen were characterized as high interventricular septal defects (H-IVSD). Light microscopy showed that the defect was caudal to the semilunar valves, with the anterior right wall of the aorta communicating with the right ventricle. Another aspect of the defect is at the level of the semilunar valves, with the right cusp or sinus of Valsalva in communication with the right ventricle. The defects are discussed more fully and methods for further study suggested.     

Dominant lethal effects of subchronic acrylamide administration in the male Long-Evans rat

Acrylamide, a widely used vinyl monomer, is well known as a neurotoxin but inactive as a mutagen in bacterial test systems. The experiments reported demonstrate that after subchronic oral dosing in the male rat, acrylamide induced significant elevations in both pre- and post-implantation loss following dominant lethal testing. These effects were seen at doses which failed to produce clinical or pathological evidence of neurotoxicity. In an accompanying cytogenetic study, no increase in chromosome aberrations was observed in spermatogonia or spermatocytes of treated animals. When spermatocytes from treated spermatogonial stem cells were analyzed, reciprocal translocations (4) were observed in the treated animals and not in the control, but the significance of this result still needs to be established.     

Teratogenic effects of lead in the mouse

Female mice of the C57B1 strain were mated and given from the first day of the pregnancy a normal diet, containing 1.1% of calcium, or a calcium-deficient one, containing 0.2% of calcium. Animals of the 2 groups were injected intra-peritoneally with 15 or 35 mg of lead acetate/kg at different times of the fetal organogenesis (8th, 9th, 10th or 12th day of the pregnancy). In the normal diet group, injection of lead increases the postimplantation mortality and the rate of skeletal anomalies among the fetuses. The anomalies are restricted to the anterior part of the axial skeleton and consist essentially in the fusion of 2 or more cervical vertebrae. In addition, lead diminishes the blood calcium levels in the pregnant females. In the calcium deficient group, all these effects of lead are considerably increased and fetuses suffer a loss of weight and delayed ossification. In the animals given such a diet but non lead-injected, the fetal weight is already diminished. However, the ossification and the rate of skeletal anomalies are not affected, and the blood calcium levels of the mothers are similar to those of the control females given a normal diet.     

Teratogenic effects of excess glucose on head-fold rat embryos in culture.

Rat embryos explanted at nine and one-half days of gestation (early head-fold stages) were cultured for 48 hours in rotating bottles containing rat serum and a gas phase. Addition of 12-15 mg/ml of D-glucose to the culture medium resulted in severe abnormalities and retarded development in a high proportion of embryos, whether or not the osmolarity increase brought about by the addition of glucose was corrected. The raised osmolarity, however, increased the frequency and severity of malformations observed. L-glucose produced no abnormalities, though embryonic development was retarded.     

Teratogenic activity of trichloroacetic acid in the rat

Trichloroacetic acid (TCA) is a by-product of the chlorine disinfection of water containing natural organic material. It is detectable in finished drinking water at levels comparable to the trihalomethanes (30-160 micrograms/L). TCA is also formed in vivo after ingestion of hypochlorite and has been identified as a major metabolite of chlorinated hydrocarbons such as trichloroethylene. The developmental effects of TCA were evaluated in the pregnant Long-Evans rat. Animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 330, 800, 1,200, or 1,800 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Live fetuses were examined for external, skeletal, and soft tissue malformation. There were no maternal deaths associated with toxicity prior to sacrifice. Weight gain during treatment was reduced at 800, 1,200, and 1,800 mg/kg. Spleen and kidney weights were increased in a dose-related manner. The mean percent of resorbed implants per litter was 34, 62, and 90 at 800, 1,200, and 1,800 mg/kg, respectively. Live fetuses showed dose-dependent reductions in weight and length. The mean frequency of soft tissue malformations ranged from 9% at the low dose to 97% at the high dose. These were principally in the cardiovascular system (interventricular septal defect, levocardia). Skeletal malformations were found only at 1,200 and 1,800 mg/kg and were mainly in the orbit. Based on these observations TCA was considered to be developmentally toxic in the pregnant rat at doses of 330 mg/kg and above.     

Teratogenic effects of diazepam in the hamster.

Pregnant hamsters were treated with different doses of oral and intravenous diazepam during the period of organogenesis. Teratogenic effects of diazepam were observed following oral treatment on days 8 and 10 and following intravenous treatment on day 11 of gestation. Types of malformations included cleft palate, exencephaly, limb anomalies, and hemorrhage. A dose-effect relationship was not observed. Comparison with reported literature seems to indicate that diazepam may be a mild teratogen in some species.     

Evaluation of olfactory and auditory system effects of the antihyperthyroid drug carbimazole in the Long-Evans rat

Carbimazole (2-carbethoxythio-1-methylimidazole) is a thiocarbamide drug used in the treatment of hyperthyroidism in humans. Side effects associated with carbimazole treatment are reported to include impaired taste, impaired olfaction, and hearing loss. The structurally similar antihyperthyroid drug methimazole (1-methyl-2-mercaptoimidazole), also reportedly associated with impaired taste and olfaction in humans, has recently been demonstrated by this laboratory to be an olfactory toxicant by both the oral and intraperitoneal routes of exposure in rodents. A systematic evaluation of sensory system effects of these compounds, either in rodents or humans, is not available in the literature. Male Long-Evans rats were used to evaluate the auditory and olfactory toxicity of carbimazole by two routes of exposure. Histopathological evaluation of nasal cavities from rats administered carbimazole via i.p. and oral routes revealed olfactory mucosal damage and early evidence of repair; a no-observed effect level (NOEL) of 100 mg/kg was observed for orally administered carbimazole. Further, these studies demonstrate evidence for the generation of the olfactory toxic metabolites of carbimazole by the olfactory mucosa itself, as incubation of carbimazole with an olfactory S9 preparation resulted in NADPH-dependent degradation of carbimazole. Evaluation of the auditory startle response in carbimazole-treated rats revealed no deficits, demonstrating that carbimazole does not cause a global loss of hearing in rats. © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 12: 305–314, 1998     

Teratogenic effects of aliphatic nitriles

Intraperitoneal injection of acrylonitrile at 1.51-2.26 mmole/kg (80-120 mg/kg) or propionitrile at 0.54-1.51 mmole/kg (30-83 mg/kg) on the morning of Day 8 of gestation in the hamster induced exencephaly, encephalocoeles, and rib fusions and bifurcations in the offspring. These doses of the aliphatic nitriles also resulted in obvious toxicity to the dams. Multiple intraperitoneal injections of sodium thiosulfate at 4.03 mmole/kg (1 gm/kg) protected both dams and embryos against toxicity. When the larger doses of either acrylonitrile or propionitrile were given in the presence of sodium thiosulfate, teratogenic effects were observed in the absence of overt signs of maternal poisoning. A survey of the literature describes many studies which demonstrate that acrylonitrile and propionitrile are converted in vivo to toxicologically significant concentrations of cyanide and that sodium thiosulfate, an established cyanide antagonist, can provide protective actions against poisoning by either acrylonitrile or propionitrile. The observations suggest that the teratogenic effects of both acrylonitrile and propionitrile are related to the metabolic release of cyanide.     

Teratogenic effects of diphenylhydantoin.

A child aged 24 months had multiple congenital abnormalities and delayed development. The 28-year-old mother had been treated since childhood with anticonvulsants. Her previous pregnancies had resulted in three early spontaneous abortions and one child with severe bilateral cleft lip and palate. This case report further suggests a relationship between maternal diphenylhydantoin use and fetal anomalies.     

Teratogenic effects of incorporated radionuclides

Experimental data on teratogenic effects induced by incorporated alpha, beta and gamma-emitters were analyzed. It was found that the radioactive substances as well as external irradiation induced teratogenic effects. Teratogenesis caused by incorporated radionuclides has some peculiarities compared to the effect caused by fetus exposure to external radiation. These peculiarities are related to the fact of the limited penetration of incorporated radionuclides via placenta barrier so the radiation fetal doses are accumulated within long period of time and radiation dose rates are relatively low. The exposure to incorporated radionuclides does not induce severe developmental defects. Most frequent developmental defects of fetus include its death, general retardation of the development and growth. In such case the earlier pregnancy term was affected by radionuclide the more severe fetal damages occur in fetus because of the gradual increase of absorbed dose even in case of single intake of radionuclide. RBEs of radionuclides if compared to that for external gamma radiation are evaluated as follows: 2-4 (tritium oxide), 20 (241Am), 50 (238Pu) and 3-5 (131I in thyroid).     

Teratogenic effects of bis-diamine on early embryonic rat heart: an in vitro study

BACKGROUND: Bis-diamine induces cardiac defects, including conotruncal anomalies in rat embryos when the agent is administered to the mother. To evaluate the teratogenic effects and mechanism of bis-diamine, we performed morphological and immunohistochemical analyses of early rat embryos cultured in medium containing bis-diamine. METHODS: The embryos were removed from mother rats on gestational day 10.5 and cultured in medium containing 1 mg of bis-diamine for 6 hr. The embryos were then cultured in medium only for another 6, 12, 18, and 42 hr, corresponding to embryonic day (ED) 11.0, 11.25, 11.5, and 12.5, respectively. Some embryos from the same mothers were used as controls and were cultured in medium only for the corresponding periods to the embryos exposed to bis-diamine. Some mother rats were given a single oral dose of 200 mg of bis-diamine on gestational day 10.5. Embryos from these pregnant rats were removed 6 hr after the oral administration of bis-diamine, and were also cultured in medium only for 6, 12, 18, and 42 hr. RESULTS: No cardiac abnormalities were detected in the controls at any stage of development. Thirty-three of 51 (65%) embryos exposed to bis-diamine and 15 of 20 (75%) embryos removed from bis-diamine-administered mothers showed abnormal cardiac development, including dilated ventricle, elongation of outflow tract, and pericardial defect on ED 11.5. Four of six (67%) embryos exposed to bis-diamine, and five of seven (71%) removed from bis-diamine-administered mothers also presented almost the same cardiac abnormalities on ED 12.5. No cardiac abnormalities were detected in bis-diamine-treated embryos before ED 11.5. In addition, the expression of neural cell adhesion molecule (N-CAM) was examined using immunohistochemical methods. Fewer N-CAM immunoreactive cells were detected in the third and fourth aortic arches in the bis-diamine-treated embryos than in controls on ED 11.5. However, more N-CAM immunoreactive cells were detected in the bis-diamine-treated embryos than in controls on ED 12.5. CONCLUSIONS: These results suggest that bis-diamine induces cardiac anomalies by delaying the migration of neural crest cells into the heart and by disturbing the proliferation of pericardial precursor during early cardiac development.