title: Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice.
abstract: The cytochrome P450 (CYP) 1 family is active toward numerous environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs). Utilizing a mouse model, null for Cyp1b1 and expressing human CYP1B1, we tested the hypothesis that hCYP1B1 is important for dibenzo[def,p]chrysene (DBC) transplacental carcinogenesis. Wild-type mCyp1b1, transgenic hCYP1B1 (mCyp1b1 null background), and mCyp1b1 null mice were assessed. Each litter had an equal number of siblings with Ahrb-1/dand Ahrd/dalleles. Pregnant mice were dosed (gavage) on gestation day 17 with 6.5 or 12 mg/kg of DBC or corn oil. At 10 months of age, mortality, general health, lymphoid disease and lung tumor incidence, and multiplicity were assessed. hCYP1B1 genotype did not impact lung tumor multiplicity, but tended to enhance incidence compared to Cyp1b1 wild-type mice (P = 0.07). As with Cyp1b1 in wild-type mice, constitutive hCYP1B1 protein is non-detectable in liver but was induced with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Wild-type mice were 59% more likely to succumb to T-cell Acute Lymphoblastic Leukemia (T-ALL). Unlike an earlier examination of the Ahr genotype in this model (Yu et al., Cancer Res, 2006;66:755-762), but in agreement with a more recent study (Shorey et al., Toxicol Appl Pharmacol, 2013;270:60-69), this genotype was not associated with lung tumor incidence, multiplicity, or mortality. Sex was not significant with respect to lung tumor incidence or mortality but males exhibited significantly greater multiplicity. Lung tumor incidence was greater in mCyp1b1 nulls compared to wild-type mice. To our knowledge, this is the first application of a humanized mouse model in transplacental carcinogenesis. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Molecular and Environmental Toxicology, Oregon State University, Corvallis, Oregon.|Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|Superfund Research Program, Oregon State University, Corvallis, Oregon.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Madeen
authors.affiliation: Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|Superfund Research Program, Oregon State University, Corvallis, Oregon.|College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
authors.forename: Hannah
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Molecular and Environmental Toxicology, Oregon State University, Corvallis, Oregon.|Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
authors.forename: Lisbeth K
authors.initials: LK
authors.lastname: Siddens
authors.affiliation: Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|Superfund Research Program, Oregon State University, Corvallis, Oregon.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Krueger
authors.affiliation: Center for Epigenetics and Disease Prevention, M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Roderick H
authors.initials: RH
authors.lastname: Dashwood
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Molecular and Environmental Toxicology, Oregon State University, Corvallis, Oregon.|Superfund Research Program, Oregon State University, Corvallis, Oregon.
authors.forename: William M
authors.initials: WM
authors.lastname: Baird
authors.affiliation: Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|Department of Nutrition and Exercise Science, Oregon State University, Corvallis, Oregon.
authors.forename: Emily
authors.initials: E
authors.lastname: Ho
authors.affiliation: Superfund Research Program, Oregon State University, Corvallis, Oregon.|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bramer
authors.affiliation: Superfund Research Program, Oregon State University, Corvallis, Oregon.|Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.affiliation: Department of Molecular and Environmental Toxicology, Oregon State University, Corvallis, Oregon.|Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|Superfund Research Program, Oregon State University, Corvallis, Oregon.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002273:Carcinogens; D002911:Chrysenes; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010920:Placenta / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
chemical_list: D002273:Carcinogens; D002911:Chrysenes; C521081:dibenzo(b,def)chrysene; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1
keywords: CYP1B1 humanized mice; PAH carcinogenesis; cytochrome P450 1B1; transplacental cancer