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.
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.
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.
In adult men the left half of the head was covered with thick heat insulation, and the right hemiface was cooled by spraying a mist of water, and vigorous fanning. The subjects were immersed up to the waist in warm water (42 degrees) to achieve hyperthermia. In control sessions the subjects were rendered slightly hypothermic by preliminary exposure to cold. Under the hypothermic condition during right skin cooling, the right Tty remained low as compared with oesophageal temperature, while the left Tty was raised. Under the hyperthermic condition right hemiface cooling maintained not only the right Tty lower than oesophageal but also, to a lesser extent the left Tty, while the skin on the left side was close to core temperature. This latter result cannot be explained by conductive cooling from the skin to the tympanic membrane and implies a vascular cooling of the left Tty originating from the other side of the head. It is concluded that selective cooling of the brain takes place during hyperthermia. The main mechanism is forced vascular convection, but conductive cooling also occurs.
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