Retinoic acid-induced stress protein synthesis in the mouse.
We have previously demonstrated that stress proteins (SPs) are synthesized in tissues in which malformations are later observed following treatment with the developmental toxicant, retinoic acid (RA), on day 11 of gestation (GD 11). These proteins were not synthesized in tissues which did not present with malformations near partuition. The purpose of the present investigation was to determine if this correlation between early SP synthesis and later malformation was present at other times during gestation. CD-1 strain mice were dosed orally with corn oil or 100 mg/kg body weight RA on GD 10 or 13. Some of the mice in each group were given an intraperitoneal injection of 3H-leucine to label embryonic protein synthesis one hour after dosing with RA. These animals were sacrificed 1.5 hour later, and embryonic protein synthesis was determined by two-dimensional gel electrophoresis followed by autoradiography. Other animals in each group were sacrificed on day 17 of gestation, and fetuses were examined for the presence of malformations. Following treatment with RA on day 10 of gestation, malformations were observed in the forelimbs, the hindlimbs and the tail; heart defects were not observed. SPs of 20-25,000 and 90,000 relative molecular mass (Mr) were synthesized in the forelimb bud and tail; in addition, a second low molecular weight (20-25,000) and a 84,000 Mr SPs were synthesized in forelimb buds. No SPs were synthesized in the hindlimb bud or the heart. Following RA treatment on GD 13, cleft palate was observed in 58% of fetuses; no other malformations were found. Proteins of 34,000, 84,000 and 90,000 Mr were synthesized in craniofacial tissue; SPs were not observed in forelimb bud, hindlimb bud, heart or tail tissues at this time. Therefore, it appears that there may be a correlation between tissue-specific SP synthesis early in organogenesis and the presence of a malformation later in gestation.
LaBorde
J B
JB
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079-9502, USA.
Pipkin
J L
JL
Hinson
W G
WG
Anson
J F
JF
Sheehan
D M
DM
Young
J F
JF
Hansen
D K
DK
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000284:Administration, Oral; D000818:Animals; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D005865:Gestational Age; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000187:drug effects; D008297:Male; D051379:Mice; D008970:Molecular Weight; D011247:Pregnancy; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*
D006360:Heat-Shock Proteins; D014212:Tretinoin