Fetal mouse Cyp1b1 and transplacental carcinogenesis from maternal exposure to dibenzo(a,l)pyrene.
Dibenzo(a,l)pyrene (DBP) is among the most potent carcinogenic polycyclic aromatic hydrocarbons. Previously, we showed that DBP administration to pregnant mice resulted in high mortality of offspring from an aggressive T-cell lymphoma. All mice that survive to 10 months of age exhibit lung tumors with high multiplicity. Recombinant cytochrome P450 (cyp) 1b1 from mice and the homologue 1B1 in humans exhibit high activity toward the metabolic activation of DBP. Targeted disruption of the cyp1b1 gene protects against most DBP-dependent cancers. Mice heterozygous for the disrupted cyp1b1 allele were used to examine the effect of cyp1b1 gene dosage on DBP transplacental carcinogenesis. Dams were treated with 1 or 15 mg/kg of DBP or 50 mg/kg of benzo(a)pyrene. Cyp1b1-null offspring did not develop lymphoma, whereas wild-type and heterozygous siblings, born to dams given the high dose of DBP, exhibited significant mortalities between 10 and 30 weeks of age. At 10 months, all groups had lung adenomas or carcinomas [9.5%, 40.3%, 25.6%, and 100% incidences for controls, benzo(a)pyrene, 1 and 15 mg/kg DBP, respectively]. Cyp1b1 status did not alter benzo(a)pyrene-dependent carcinogenesis. At 1 mg/kg DBP, cyp1b1 status altered the incidence of lung tumors (19.0, 27.8, and 28.6% for nulls, heterozygous, and wild-type, respectively). At 15 mg/kg, tumor multiplicities in cyp1b1 wild-type (9.3) and heterozygous (9.5) offspring were nearly twice that of cyp1b1-null siblings (5.0). These data confirm that cyp1b1 bioactivation of DBP occurs in fetal target tissues, following transplacental exposure, with the thymus and lung as primary and secondary targets, respectively.
Castro
David J
DJ
Department of Environmental and Molecular Toxicology, Oregon State University, ALS 1007, Corvallis, OR 97331-7301, USA.
Baird
William M
WM
Pereira
Clifford B
CB
Giovanini
Jack
J
Löhr
Christiane V
CV
Fischer
Kay A
KA
Yu
Zhen
Z
Gonzalez
Frank J
FJ
Krueger
Sharon K
SK
Williams
David E
DE
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D065633:Cytochrome P-450 CYP1B1; D005260:Female; D046689:Fetal Mortality; D005333:Fetus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000151:congenital / Q000235:genetics / Q000401:mortality; D008223:Lymphoma / Q000139:chemically induced / Q000151:congenital / Q000235:genetics / Q000401:mortality; D018811:Maternal Exposure / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000139:chemically induced* / Q000151:congenital / Q000235:genetics / Q000401:mortality; D011247:Pregnancy; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000151:congenital / Q000235:genetics / Q000401:mortality
D001580:Benzopyrenes; D002273:Carcinogens; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; C041517:dibenzo(a,l)pyrene