DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in fetal tissues of patas monkeys after transplacental exposure.
Transplacental genotoxicity of the heterocyclic amine food-derived mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) has been investigated by (32)P-postlabeling assay for IQ-DNA adducts in maternal liver, placenta, and several fetal tissues of patas monkeys, after exposure to 15, 35, or 50 mg/kg IQ near the end of gestation or to the highest dose in the first or second trimester. Dose-dependent adduct formation occurred in all tissues, with the highest levels occurring in maternal liver. Adduct amounts were similar among fetal tissues and placenta, except for lower levels in fetal brain and slightly more adducts in fetal liver. Adducts in placenta, fetal liver, lung, kidney, skin, and adrenal gland, but not in maternal liver or fetal brain, increased significantly as gestation progressed. Pretreatment with phenobarbital, which induces CYP enzymes that detoxify IQ, decreased adducts in maternal liver and possibly placenta, but not in fetal tissues. The CYP inducer beta-naphthoflavone caused a significant increase in IQ-DNA adducts in fetal lungs. Regression analysis suggested that IQ activation in maternal and fetal liver and possibly placenta contributed to adduct formation in fetal tissues; adducts in placenta and/or fetal liver were strong predictors for those in most fetal tissues. The results indicate that exposure of pregnant primates to IQ results in DNA adduct formation in most fetal tissues, especially late in gestation; that upregulation of maternal detoxification does not provide fetal protection; and that adducts in placenta indicate adduct levels in fetal tissues.
Josyula
S
S
Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, Texas 77555-1110, USA.
Lu
L J
LJ
Salazar
J J
JJ
Nerurkar
P V
PV
Jones
A B
AB
Grady
J J
JJ
Snyderwine
E G
EG
Anderson
L M
LM
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D016669:Erythrocebus; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D009153:Mutagens / Q000378:metabolism*; D009928:Organ Specificity; D010634:Phenobarbital / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011804:Quinolines / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital