Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type,Cyp1b1knockout, andCYP1B1humanized 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/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), but in agreement with a more recent study (Shorey et al., Toxicol. Appl. Pharmacol., 2013), 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.

Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane

“…C57BL/6J (Ahr b/b ) mice were bred with 129 (Ahr d/d ) mice and dams dosed with the potent PAH, DBC (30-times more potent that BaP), 2-3 days prior to parturition. Offspring that were exposed in utero (and to some degree during lactation) developed an aggressive T-cell acute lymphoblastic leukemia (T-ALL) which began at 3 months of age (92)(93)(94). All of the surviving offspring exhibited multiple lung tumors at 10 months of age.…”

“…All of the surviving offspring exhibited multiple lung tumors at 10 months of age. The severity of the response was a function of both the maternal and offspring phenotype (i.e., Ahr b allele is "responsive" and Ahr d "non-responsive") (92) and was absent in Cyp1b1 null offspring (93). Administration of phytochemicals known to be chemopreventive in adult models to the maternal diet (gestation day 9 to weaning), including I3C (95,96), green tea (97) and chlorophyllin (98) provided protection for the offspring from both the young adult onset T-ALL mortality and the mid-life lung cancer.…”

CYP1B1 converts procarcinogens into genotoxins in Saccharomyces cerevisiae

“…Abundant evidence, derived from epidemiological human studies, cell cultures, and transgenic mice, suggests that CYP1B1 has a prominent role in activating a wide variety of procarcinogens (Shimada et al, 1996). CYP1B1 knock-out mice are more resistant to the carcinogenic effects of polyaromatic hydrocarbons, such as 7, 12-dimethylbenz[a]anthracene (DMBA, Buters et al 1999), while CYP1B1 humanized mice have a higher incidence of dibenzo[def,p]chrysene-associated cancers (Madeen et al, 2017). Human CYP1B1 polymorphisms have been correlated with the higher incidence of endometrial, colon, lung and laryngeal cancer (Trubicka et al, 2010; Chen et al, 2015; Elfaki et al, 2018); among Asians, the CYP1B1 G119T allele is a risk factor for prostate and breast cancer (Li et al, 2015).…”