Effects of concurrent exposure to 3-methylcholanthrene and vitamin A on fetal development in rats.
To investigate the effect of the environmental pollutants, polycyclic aromatic hydrocarbons (PAHs), on retinoic acid-induced teratogenesis, all-trans-retinoic acid (RA) dissolved in corn oil (120 mg/kg) was administered orally to pregnant rats at the 11th day of gestation with and without the prior intraperitoneal treatment with 10 mg/kg 3-methylcholanthrene (3-MC) for 3 days. Dams were killed on the 20th day of pregnancy. The examinations of fetuses revealed that 3-MC barely enough to cause induction of P-450 in pregnant dams had profound embryo-toxic effects: the fetal resorption amounted to approximately 60% of total number of implantations. The fetuses survived weighed less than the control fetuses. All of RA-treated mothers had fetuses with abnormalities, and the main malformations were absence of tail (100%), caudal and sacral malformations (100%), and cleft palate (42%). Pregnant dams received both 3-MC and RA had a reduced severity of tail anomaly (33%), while the rest, 67%, had short vestigial tail. Caudal and sacral malformations were detected but at a milder degree. We did not observe cleft palate in this group. The concurrent treatment of dams with 3-MC and RA led to an increased inducibility of cytochrome P-450 and subsequently, CYP1A1 dependent enzyme activity higher than those observed after the injection of 3-MC alone. UDP-glucuronyl-transferase activity was also markedly induced in concurrent 3-MC and RA group higher than that in 3-MC alone. We suggest that the induction of P-450 and alteration of metabolic enzyme activities may play an important role in reducing the teratogenic potency of RA. However, RA-treatment did not retard the embryo-toxic effect of 3-MC but rather potentiated.
Khlood
E B
EB
Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Miyoshi
H
H
Iwata
H
H
Kazusaka
A
A
Kon
Y
Y
Hadid
A H
AH
Moustafe
E K
EK
Ghonim
M H
MH
Fujita
S
S
D000014:Abnormalities, Drug-Induced; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D005333:Fetus / Q000187:drug effects*; D008748:Methylcholanthrene / Q000633:toxicity*; D008862:Microsomes, Liver / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*; D014801:Vitamin A / Q000633:toxicity*
D013723:Teratogens; D014801:Vitamin A; D008748:Methylcholanthrene; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1