Dataset Information

Induction of active hepatic cytochrome P450 enzymes in mice exposed to benzo[a]pyrene or environmental mixtures of polycyclic aromatic hydrocarbons

ABSTRACT: Cytochrome P450 enzymes play an important role in bioactivating or detoxifying polycyclic aromatic hydrocarbons (PAHs). We exposed mice to doses of benzo[a]pyrene (BaP) or a mixture of PAHs to characterize dose- and time-response relationships of specific cytochrome P450s. Mice exposed to the highest PAH exposures exhibited 1.7-5-fold higher intrinsic clearance rates for BaP, compared to controls, and higher Vmax values, indicating higher amounts of enzymes capable of metabolizing BaP. This study demonstrates that PAHs induce enzymes in dose- and time-dependent patterns in animal models at exposure levels researchers use to characterize hazards and at relevant human exposure levels to PAH mixtures found at Superfund sites. Accounting for these potential changes in enzyme profiles, relative rates of PAH bioactivation and detoxification, and resulting risk will help reduce uncertainty and improve risk assessments for PAHs at contaminated sites.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Matthew Monroe

LAB HEAD: Aaron T Wright

PROVIDER: PXD019472 | Pride | 2022-10-13

REPOSITORIES: Pride

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Publications

Exposure to an Environmental Mixture of Polycyclic Aromatic Hydrocarbons Induces Hepatic Cytochrome P450 Enzymes in Mice.

Stoddard Ethan G EG Nag Subhasree S Martin Jude J Tyrrell Kimberly J KJ Gibbins Teresa T Anderson Kim A KA Shukla Anil K AK Corley Richard R Wright Aaron T AT Smith Jordan N JN

Chemical research in toxicology 20210902 9

Cytochrome P450 enzymes (CYPs) play an important role in bioactivating or detoxifying polycyclic aromatic hydrocarbons (PAHs), common environmental contaminants. While it is widely accepted that exposure to PAHs induces CYPs, effectively increasing rates of xenobiotic metabolism, dose- and time-response patterns of CYP induction are not well-known. In order to better understand dose- and time-response relationships of individual CYPs following induction, we exposed B6129SF1/J mice to single or r ...[more]

PMID: 34472326

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Project description:The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4 nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1 ) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response of mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by 32P post- labeling, did not correlate with tumor incidence. PAH dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p<0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs). Gene expression was measured in mouse skin 12 hours after initiation with PAH carcinogens. The following initiation treatments were applied to mice (N=4 or 5 per biological replicates treatment); toluene vehicle control (200 M-NM-<l), BaP 400 nmol (100 M-NM-<g), DBC 4 nmol (1.2 M-NM-<g), or to mixtures of environmental PAH mixtures containing diesel particulate extract, coal tar extract, or cigarette smoke condensate.

Project description:Polycyclic aromatic hydrocarbons (PAHs) are widely distributed, carcinogenic environmental contaminants produced as a consequence of the incomplete combustion of fossil fuels. Benzo[a]pyrene (BaP) is a very extensively studied prototypical PAH. We recently reported a complete lack of change in microRNA (miRNA) expression in adult mouse liver following oral gavage with BaP despite a robust transcriptome response. We hypothesized that hepatic miRNAs may not be highly responsive to the treatment. Here, we analyse the pulmonary mRNA and miRNA response to BaP in the same mice. Adult male B6C3F1 mice were exposed to 5, 50, 150 and 300 mg/kg BaP by oral gavage for three consecutive days and sacrificed 4 or 24 hours after the last exposure. Serum clinical chemistry and DNA adduct levels in whole lung and liver tissues were analysed at both the time points for all the doses. Acute exposure to BaP resulted in modest decreases in serum inorganic phosphorous, calcium, glucose, alkaline phosphatase and lactate dehydrogenase in animals treated with 300 mg/kg BaP. 32P postlabeling of DNA revealed similar increases in BaP-DNA adducts in both lungs and livers of exposed mice in a dose dependent manner at the 4 hour time point. Using DNA microarrays, pulmonary mRNA and miRNA expression was analysed 4 hours after the final exposure. Over 1,000 genes were statistically differentially expressed (fold change > 1.5 and p < 0.05), encompassing numerous pathways including: oxidative stress, xenobiotic metabolism, cell proliferation, cell cycle, B and T-cell receptor signalling and primary immunodeficiency signalling pathways. Analysis of miRNA profiles revealed downregulation of miR-150, miR-142-5p, 142-3p and upregulation of miR-34c and miR-29b. These miRNAs are involved in various biological processes including immune response, cell proliferation and cell cycle, which are also the main pathways affected at the gene expression level. As BaP exposure does not result in hepatocarcinogenicity, but does cause lung cancer, these miRNAs may play an important role in the outcome of the exposure and be more predictive of carcinogenesis. Keywords: mRNA, miRNA, Pulmonary, non-target tissue, Toxicogenomics, Benzoapyrene

Dataset Information

Induction of active hepatic cytochrome P450 enzymes in mice exposed to benzo[a]pyrene or environmental mixtures of polycyclic aromatic hydrocarbons

Publications

Exposure to an Environmental Mixture of Polycyclic Aromatic Hydrocarbons Induces Hepatic Cytochrome P450 Enzymes in Mice.

Similar Datasets

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