Prenatal exposure of the developing rat brain to methylazoxymethanol acetate results in the formation of ectopic groups of pyramidal neurons in the subfields CA1 and CA2 of the mature hippocampal formation. These ectopic neurons are situated in regions of increased vascularization and increased activity of cytochrome oxidase, as demonstrated histochemically. Both these findings suggest that there may be an abnormality of distribution or intensity of oxidative metabolic activity in the ectopic pyramidal neurons found in these animals.

Abnormalities, Drug-Induced↗

PubMed1986

Isotretinoin embryopathy and the cranial neural crest: an in vivo and in vitro study.

Severe congenital malformations have been associated with the inadvertant use in early pregnancy of a new dermatological drug, isotretinoin. We present proposals for the pathogenesis of this embryopathy based on the study of animal models. The characteristic malformations of the face, thymus, and great vessels were induced in mice by prenatal exposure to the drug during the early somite stages of development. From histological examination of mouse embryos it was shown that the drug directly interferes with the development of cranial neural crest cells. Subsequent deficiency of crest cell-derived mesenchyme adequately explains most of the observed malformations. Rat embryo culture studies showed that, when used at concentrations of 500 ng/ml, both isotretinoin and its main metabolite in the human, 4-oxo-isotretinoin, induce malformations similar to those seen in vivo. Since during normal repetitive dosing in the human the mean trough blood concentration of isotretinoin ranges from 132 to 196 ng/ml, while 4-oxo-isotretinoin ranges from 610 to 791 ng/ml, it is likely that the metabolite plays a major role in the induction of the isotretinoin embryopathy.

Abnormalities, Drug-Induced↗

PubMed1985

The induction of microphthalmia, encephalocele, and other head defects following hyperthermia during the gastrulation process in the rat.

The aim of this study was to ascertain whether there is a period during early embryonic development of the rat that is particularly sensitive to hyperthermia. Pregnant Sprague-Dawley rats were partially immersed in a water bath at 43.5 degrees C until their core temperatures, monitored by a rectal thermistor probe, were elevated to 43.5 degrees C. The procedure was repeated 6 hours later. The regimen of two heatings was performed over a range of development from early gastrulation (8 days 18 hours) to about the 12 somite stage (10 days 18 hours). The rats were killed on days 17-19 and the fetuses were examined. Each group contained a minimum of five litters. The main teratogenic effect of the hyperthermia was the induction of one or more head defects, notably microphthalmia, encephalocele (either a single, large, parietal encephalocele or multiple small protuberances), and maxillary hypoplasia. Microphthalmia was the most common defect with approximately 90% of surviving fetuses having small eyes when heating occurred between 9 days 6 hours and 10 days 0 hours (9.06 and 10.00). Encephaloceles were induced by heating between 9.00 and 10.00 with a peak sensitivity between 9.12 and 9.18 when 57% of surviving fetuses were affected. Maxillary hypoplasia resulted from heating between 9.06 and 10.06 with up to 20% of surviving fetuses being affected. Control rats were exposed to the same experimental procedure in a water bath at 38 degrees C on 9.12 and 9.18, the gestational time most sensitive to hyperthermia induced malformations. There were no abnormal fetuses in the controls. The critical period identified spans 9 days 6 hours to 10 days 0 hours gestational age. In developmental terms this includes a large proportion of the gastrulation process.

Animals↗

PubMed1985

Hyperthermia as a teratogen: parameters determining hyperthermia-induced head defects in the rat.

This study determined the relationship between the duration and extent of temperature elevation, during a critical period of rat embryonic development, and the induction of congenital malformations. Pregnant Sprague-Dawley rats, at 9 days 12 hours gestation (gastrulation stage), were partially immersed in a water bath until their core temperature, monitored by a rectal thermistor probe, was elevated to a nominated temperature. Seven temperatures were tested from 40.5 degrees C to 43.5 degrees C, elevations of 2.0-5.0 degrees C in core temperature. Various durations at each of these temperatures were tested for potential teratogenicity. A single elevation of 5.0 degrees C or 4.5 degrees C needed only a "spike" in duration to be teratogenic, 4.0 degrees C was teratogenic within 5 minutes, 3.5 degrees C within 10 minutes, 3.0 degrees C within 20 minutes, and 2.5 degrees C within 1 hour. An elevation of 2.0 degrees C for 8 hours was not teratogenic. Microphthalmia was the most common malformation at all teratogenic temperatures and was frequently the only malformation seen at the shortest time exposure for a particular temperature. Encephalocele, facial clefting, and maxillary hypoplasia were the other frequently seen malformations. Five control rats were placed in the water bath for 2 hours at 38 degrees C so that their core temperature was not elevated. All the control fetuses were normal. An elevation of 2.5 degrees C for 1 hour was the threshold combination for teratogenesis. As the temperature increased above a 2.5 degrees C elevation the necessary duration of exposure for teratogenesis decreased.

Animals↗

PubMed1985

Tumors and polycystic renal disease in two captive woodchucks (Marmota monax).

Hepatocellular carcinoma, polycystic renal disease and pneumonia are reported in an aged woodchuck, and a metastatic fibrosarcoma is reported in a relatively young animal born and raised in the laboratory.

Animals↗

PubMed1985

The effects of acute or chronic cadmium exposure on the adult mouse CNS: a freeze-fracture study.

The effect of acute Cd exposure (0.5-12 mg CdCl2/kg body wt. for six hours) or chronic Cd exposure (40 ppm in the drinking water for 3 weeks) on the CNS of adult mice was investigated quantitatively by the use of the freeze-fracture technique to examine the nuclear membrane of cells from the cerebral cortex. Intramembrane particle density and nuclear pore density was determined for both the P face of the inner membrane and the E face of the outer membrane from control and experimental animals. The changes observed for both groups of experimental animals were similar in that particle numbers for both P and E faces were significantly increased over control values while nuclear pore numbers were unaffected. For the acute doses the increases were dose-dependent.

Animals↗

PubMed1984

Hyperthermia and the induction of neural tube defects in mice.

The aim of this study was to examine some parameters determining the teratogenicity of hyperthermia. Pregnant inbred (C57B1/6J and CBA/Ca/T6) and outbred (QS) mice were partially immersed in a water bath at 43-43.5 degrees C until their core temperature, monitored by a rectal thermister probe, was elevated to 43 degrees C for the inbred mice and 43.5 degrees C for the outbred mice. The procedure was repeated 6 h later. The regimen of 2 heatings was performed over a range of development from pregastrulation to about the 24 somite stage. The mice were killed on day 19, and the fetuses were examined. Exencephaly was the common malformation seen in each strain. It occurred at a maximum incidence of 34% in the QS mice, 14% in the CBA strain, and 20% in C57B1 mice. For the CBA and QS mice 4 to 11-15 somites was the most heat sensitive stage of development for the induction of exencephaly while in the C57B1 mice the preceding 24 hr of development were most sensitive. Control mice were exposed to the same experimental procedure in a water bath at body temperature at the most sensitive stage of development for the strain. There were no instances of exencephaly in the controls. The sex of all fetuses was determined and revealed a high female/male ratio among the fetuses with exencephaly (2.1 for the QS mice, 1.7 for the CBA mice, and 3.1 for the C57B1 mice) compared with a ratio of approximately 1.0 for all fetuses. Analysis in the QS mice indicated that the predominance of female exencephalics was probably due to prenatal loss of male embryos.

Abnormalities, Multiple↗

PubMed1984

Alcohol and congenital heart defects: an experimental study in mice.

Pregnant mice were exposed to a single dose of alcohol (0.03 ml of 25% alcohol X g-1 mouse) or two doses (2 X 0.015 ml of 25% alcohol X g-1 mouse) 4 h apart, by intraperitoneal injection or by gavage, on days 7, 8, 9 or 10 of gestation. The mice were killed on the day before term and the fetuses examined for heart defects. Alcohol exposure on day 8, 9 or 10 of gestation caused a high incidence of ventricular septal defects (60%, 75% and 15% respectively). Defects of both the membranous and muscular parts of the septum were seen as well as more complex ventricular septal defects involving the great vessels. Day 7 was resistant to the induction of heart defects. This study has demonstrated that a relatively short exposure to high doses of alcohol during pregnancy in mice can cause congenital heart defects. This has important implications both as a possible cause of congenital heart anomalies in humans and for the counselling of mothers of affected children.

Abnormalities, Drug-Induced↗

PubMed1983

Fetal alcohol syndrome. A great paediatric imitator.

Twenty children affected by prenatal exposure to alcohol are described. Their mothers either suffered from chronic alcoholism, or were binge or heavy drinkers while pregnant. Only in nine mothers (45%) was alcohol abuse recognized and associated with their babies' anomalies in the first months after birth; in some, the diagnosis of fetal alcohol syndrome was delayed for many years. Alcohol abuse in pregnancy is probably a significant cause of birth and developmental defects in Australian children.

Alcoholism↗

PubMed1983

Teratogenesis after acute alcohol exposure in cultured rat embryos.

In order to investigate whether alcohol has teratogenic properties, rat embryos were cultured in vitro during their organogenetic period and exposed to ethanol at 200-800 mg% culture medium for the 48 hours of culture (0-24 somite stage) or to 600-800 mg% for 24 hours, or 6-hour periods. Exposure to alcohol throughout the entire 48-hour culture period or the first 24-hour period (0-12 somites) produced marked growth retardation, particularly of the head region in a dose-dependent manner, but did not prevent neural tube closure. Exposure to high levels of ethanol during specific 6-hour periods of early organogenesis (three to nine somites) prevented closure of the neural tube in 30% of cultured rat embryos, indicating a direct teratogenic action of ethanol. These results implied an effect of ethanol on embryonic development, independent of maternal metabolism. The 6-hour exposure experiments demonstrated that high doses of ethanol during specific periods of organogenesis can be teratogenic.

Animals↗

PubMed1983

Some teratogenic properties of ethanol and acetaldehyde in C57BL/6J mice: implications for the study of the fetal alcohol syndrome.

To investigate the teratogenic effect of acute alcohol exposure, pregnant C57BL/6J mice were exposed to 25% ethanol (either two doses of 2.9g/kg or one dose 5.8g/kg) during the organogenic period either by intraperitoneal injections or by intubation. The incidence of malformations varied according to (1) the stage of embryonic development at the time of exposure, (2) the route of administration of the alcohol, and (3) the amount of alcohol given and the time period over which it was administered. Oral doses of alcohol were teratogenic although less so than the same dose given intraperitoneally, and two intraperitoneal doses four hours apart produced significantly more malformation than the same two doses six hours apart. The primary metabolite of alcohol, acetaldehyde, was also investigated for its teratogenicity. It was found that one or two doses of four percent acetaldehyde (0.32g/kg), administered intraperitoneally were teratogenic. A further attempt was made to raise blood acetaldehyde levels by exposing mice to disulfiram, an inhibitor of acetaldehyde dehydrogenase, prior to administration of alcohol. The disulfiram pretreatment did not increase the malformation rate. Treatment with alcohol on day 7 or 8 caused a variety of facial abnormalities, some of which were comparable to those seen in children with fetal alcohol syndrome. Exposure on day 9 or 10 resulted in limb defects. The results suggest that one or more episodes of heavy maternal drinking at critical periods in pregnancy may severely damage the embryo and may produce many features of the fetal alcohol syndrome.

Acetaldehyde↗

PubMed1983

Cadmium uptake and distribution in mouse embryos following maternal exposure during the organogenic period: a scintillation and autoradiographic study.

Pregnant C57BL/6J mice were given a single intraperitoneal injection of either a teratogenic (2,400 micrograms Cd/kg) an intermediate (40 micrograms Cd/kg) or a trace dose (0.66 micrograms Cd/kg) of cadmium chloride (CdCl2) on day 9 of gestation; each dose contained 109CdCl2 (20 microCi). The mice were euthanized at various times after Cd exposure, and the amount of Cd in the embryos was determined in a gamma counter. For all three doses a low, but similar, percentage of the dose rapidly entered the embryos; levels then decreased during the next 11 hours, only to rise again by 24 hours and continue to rise for the remainder of the pregnancy. When the Cd content was related to embryonic weight the Cd concentration was at its highest level after 1 hour and then decreased rapidly and continued to decrease for the rest of pregnancy. Autoradiographic studies showed that the teratogenic dose of Cd entered all tissues of the embryos but was particularly localized in cells of the neural tube, limb buds, and gut. By 12 hours, cell damage was seen in the embryos but the affected cells were not necessarily the heavily labelled cells. In embryos exposed to the nonteratogenic dose the highest Cd accumulation was seen in the embryonic gut and limb bud ectoderm but all tissues showed a low level of labelling.

Animals↗

PubMed1982

The classification and development of cadmium-induced limb defects in mice.

Explore the source record for details and available documents.

Abnormalities, Drug-Induced↗

PubMed1981

A new mouse mutant showing cerebellar abnormalities.

This paper describes a previously unreported recessive mutation in mice which, in the homozygous state, caused an abnormal posture, characterised by extension and abduction of the limbs on one side. This position alternated causing the mice to fall to one side or the other. The only histological abnormality noted, in the slightly smaller brains of the mutants, was a displacement and disarrangement of the Purkinje cells into the granular layer, in parts of the nodulus.

Animals↗