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.
D000818:Animals; D001831:Body Temperature; D002971:Cleft Lip / Q000209:etiology; D002972:Cleft Palate / Q000209:etiology; D000013:Congenital Abnormalities / Q000209:etiology*; D004677:Encephalocele / Q000209:etiology; D005260:Female; D005865:Gestational Age; D006358:Hot Temperature / Q000009:adverse effects*; D008437:Maxilla / Q000002:abnormalities; D008850:Microphthalmos / Q000209:etiology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors