Embryonic prostaglandin H synthase-2 (PHS-2) expression and benzo[a]pyrene teratogenicity in PHS-2 knockout mice.
The developmental role of prostaglandin H synthase-2 (PHS-2), which converts xenobiotics such as benzo[a]pyrene (B[a]P) to toxic free radical intermediates, is poorly understood. In this study, we determined the embryonic expression and teratological relevance of PHS-2 in pregnant CD-1 and B6/129S7 PHS-2 knockout mice. Wild-type (+/+) B6/129S7 dams given B[a]P on gestational day (GD) 10 had three times more fetal malformations than did +/- PHS-2-deficient dams (P<0.05). GD 10-13 CD-1 embryos had high PHS-2 protein expression, and both + /+ and +/- GD 19 B6/129S7 fetuses had more B[a]P-initiated malformations and postpartum lethality than did -/- littermates (P<0.05). Thus, embryonic PHS-2 is expressed constitutively during organogenesis and contributes substantially to B[a]P teratogenicity.
Parman
Toufan
T
Faculty of Pharmacy and, Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
Wells
Peter G
PG
D000014:Abnormalities, Drug-Induced / Q000201:enzymology / Q000378:metabolism / Q000401:mortality; D000818:Animals; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D051546:Cyclooxygenase 2; D004622:Embryo, Mammalian / Q000201:enzymology*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005838:Genotype; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism*; D013045:Species Specificity; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity*
D007527:Isoenzymes; D013723:Teratogens; D001564:Benzo(a)pyrene; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases