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Mol Carcinog. 2017 Jan;56(1):163-171. doi: 10.1002/mc.22480. Epub 2016 Mar 17.

Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice.

Author information

  • 1Department of Molecular and Environmental Toxicology, Oregon State University, Corvallis, Oregon.
  • 2Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
  • 3Superfund Research Program, Oregon State University, Corvallis, Oregon.
  • 4College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
  • 5Center for Epigenetics and Disease Prevention, M.D. Anderson Cancer Center, Houston, Texas.
  • 6Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • 7Department of Nutrition and Exercise Science, Oregon State University, Corvallis, Oregon.
  • 8Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.

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/d and Ahrd/d alleles. 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.

KEYWORDS:

CYP1B1 humanized mice; PAH carcinogenesis; cytochrome P450 1B1; transplacental cancer

PMID:
26990437
DOI:
10.1002/mc.22480
[PubMed - in process]
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