TitleDibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice.
Publication TypeJournal Article
Year of Publication2017
AuthorsMadeen, EP, Löhr, CV, You, H, Siddens, LK, Krueger, SK, Dashwood, RH, Gonzalez, FJ, Baird, WM, Ho, E, Bramer, L, Waters, KM, Williams, DE
JournalMol Carcinog
Volume56
Issue1
Pagination163-171
Date Published2017 01
ISSN1098-2744
KeywordsAnimals, Carcinogenesis, Carcinogens, Chrysenes, Cytochrome P-450 CYP1B1, Female, Gene Expression Regulation, Neoplastic, Humans, Lung, Lung Neoplasms, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Placenta, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Pregnancy, Pregnancy Complications, Neoplastic
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 Ahr and Ahr 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.

DOI10.1002/mc.22480
Alternate JournalMol. Carcinog.
PubMed ID26990437
PubMed Central IDPMC5457169
Grant ListP01 CA090890 / CA / NCI NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States