PNNL

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 a human CYP1B1 transgene, we tested the hypothesis that hCYP1B1 is important for dibenzo[def,p]chrysene (DBC) transplacental carcinogenesis. Wild-type mCyp1b1, transgenic hCYP1B1(on a mCyp1b1 null background), and mCyp1b1 null mice were assessed, each litter containing a 1:1 ratio of siblings with Ahrb-1/d and Ahrd/d alleles. Pregnant mice were orally gavaged on gestation day 17 with 6.5 or 12 mg/kg of the PAH, DBC, and compared to corn oil controls. The offspring, born on gestation day 19, were evaluated at 10 months of age for mortality, general health, lymphatic diseases, and lung tumor incidence and multiplicity. Wild type mice were 59% more likely to succumb to T-cell Acute Lymphoblastic Leukemia (T-ALL). The Ahr genotype was not a significant factor in lung tumor incidence, multiplicity, or mortality. Gender was not a significant factor in lung tumor incidence or mortality but males exhibited a significantly greater lung tumor multiplicity. The hCYP1B1 genotype did not impact lung tumor multiplicity, but lung tumor incidence was greater in mCyp1b1 nulls compared to wild-type mice. Transgenic hCYP1B1 mice were more likely to develop lung tumors than Cyp1b1 wild-type but this did not reach statistical significance (p = 0.07).