Oral benzo[a]pyrene‐induced cancer: Two distinct types in different target organs depend on the mouse Cyp1 genotype

Abstract

Benzo [a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1 and CYP1B1) can both detoxify PAHs and activate them to cancer-causing reactive intermediates. Following high dosage of oral BaP (125 mg/kg/day), ablation of the mouse Cyp1a1 gene causes immunosuppression and death within~28 days, whereas Cyp1(1/1) wild-type mice remain healthy for >12 months on this regimen. In this study, male Cyp1(1/1) wild-type, Cyp1a1(2/2) and Cyp1b1(2/2) single-knockout and Cyp1a1/1b1(2/2) double-knockout mice received a lower dose (12.5 mg/kg/day) of oral BaP. Tissues from 16 different organs-including proximal small intestine (PSI), liver and preputial gland duct (PGD)-were evaluated; microarray cDNA expression and >30 mRNA levels were measured. Cyp1a1(2/2) mice revealed markedly increased CYP1B1 mRNA levels in the PSI, and between 8 and 12 weeks developed unique PSI adenomas and adenocarcinomas. Cyp1a1/1b1(2/2) mice showed no PSI tumors but instead developed squamous cell carcinoma of the PGD.

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

“…Therefore, we decreased the daily oral BaP dose of 125 mg/ kg/d to 12.5 mg/kg/d; this dose allowed Cyp1a1(2/2) mice to live beyond 20 weeks of age instead of dying at 28-32 days when given the higher BaP dose (Shi et al, 2010b). Adenocarcinoma of the PSI developed in Cyp1a1(2/2) mice between 8 and 12 weeks of oral BaP (12.5 mg/kg/d).…”

“…Adenocarcinoma of the PSI developed in Cyp1a1(2/2) mice between 8 and 12 weeks of oral BaP (12.5 mg/kg/d). Interestingly, in Cyp1a1/1b1(2/2) double-knockout mice between 8 and 12 weeks on this same BaP oral dose, no GI tract cancer occurred; however, squamous cell carcinoma (SCC) of the preputial gland duct (PGD) appeared (Shi et al, 2010b) (Table 3).…”

“…In addition to characterizing the tumors histologically, we performed cDNA microarray analyses of the PSI and PGD during formation of the malignancies (Shi et al, 2010b;Gálvez-Peralta et al, 2013). Zero versus 4-week-interval time points of oral BaP (12.5 mg/kg/d) were compared between relevant genotypes.…”

“…Many of the top-ranked upregulated and downregulated genes during PSI adenocarcinoma formation are discussed in detail by Shi et al (2010b). Genes involved in inflammation and acute phase response were among those strikingly upregulated by daily oral BaP after 4 weeks.…”

Evaluating Breast Cancer Risk under Exposure to Environmental Estrogen-Like Chemicals

“…TCDD was classified as a group 1 carcinogen by the International Agency for Research on Cancer in 1997 [60,64]. As a carcinogen for humans, dioxins can combine with the aryl hydrocarbon receptor (AhR) to activate and induce the AhR pathway mediating cytochrome P450 (CYP1) expression, disrupting endocrine functions and thereby leading to adductive and oxidative DNA damage and resulting in mutagenesis as an incentive for diseases [65][66]. Some studies showed that dioxins played a protective role in breast cancer development because TCDD can induce the expression of CYP1A1 and CYP1B1 to catalyze estradiol (E2) metabolism, leading to reduced E2 levels in breast tissue cells [9,[67][68].…”