Dataset Information

Changes of serum amino acid profiles by an epidermal growth factor receptor mutation and benzo[a]pyrene in mouse lung tumorigenesis.

ABSTRACT: Studies suggest that gene mutation and carcinogen exposure contribute to lung tumorigenesis including a mutation of epidermal growth factor receptor (EGFR) and exposure to benzo[a]pyrene (BaP). However, the interaction between EGFR mutation and BaP exposure during lung tumorigenesis is unclear. Metabolomics has become an important tool in clinical research and has been utilized to help our understanding of mechanisms and to identify indicators of cancers. This study's aim was to identify the changes in metabolite profiles in mice associated with an EGFR exon 21 deletion and/or BaP treatment-induced lung tumorigenesis. While the EGFR mutation increased the incidence of lung adenoma in transgenic mice (EGFR mutant mice) at 32 weeks of age, exposure to BaP caused the onset of lung tumorigenesis in these mice as early as 16 weeks after exposure. Using a metabolomics strategy involving liquid chromatography-mass spectrometry in conjunction with principal component analysis and confirmation by liquid chromatography triple quadrupole tandem mass spectrometry, we demonstrated that the serum amino acid profiles of these mice were changed. A total of eight amino acid concentrations were lower in EGFR mutant mice than in wild-type mice at 32 weeks of age. Five amino acids were lower in tumor-bearing mice than in non-tumor-bearing EGFR mutant mice at 10th week post-treatment of BaP, namely phenylalanine, tyrosine, alanine, proline, and threonine. Our results suggest that gene mutation and carcinogen exposure-induced lung adenomas share some common mechanisms. Changes in serum amino acid profiles may be early indicators of lung tumorigenesis.

SUBMITTER: Lin P

PROVIDER: S-EPMC6062176 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Changes of serum amino acid profiles by an epidermal growth factor receptor mutation and benzo[<i>a</i>]pyrene in mouse lung tumorigenesis.

Lin Pinpin P Chen Yi-Rong YR Chen Chao-Yu CY Chang Ya-Ting YT Chen Jhih-Sheng JS Tsai Ming-Hsien MH Kuo Cheng-Chin CC Lee Hui-Ling HL

Toxicology research 20160517 4

Studies suggest that gene mutation and carcinogen exposure contribute to lung tumorigenesis including a mutation of epidermal growth factor receptor (EGFR) and exposure to benzo[<i>a</i>]pyrene (BaP). However, the interaction between EGFR mutation and BaP exposure during lung tumorigenesis is unclear. Metabolomics has become an important tool in clinical research and has been utilized to help our understanding of mechanisms and to identify indicators of cancers. This study's aim was to identify ...[more]

PMID: 30090424

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Project description:Polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (B[a]P) are among the most abundant environmental pollutants, resulting in continuous exposure of human skin and its microbiota. However, effects of the latter on B[a]P toxicity, absorption, metabolism, and distribution in humans remain unclear. Here, we demonstrate that the skin microbiota does metabolize B[a]P on and in human skin in situ, using a recently developed commensal skin model. In this model, microbial metabolism leads to high concentrations of known microbial B[a]P metabolites on the surface as well as in the epidermal layers. In contrast to what was observed for uncolonized skin, B[a]P and its metabolites were subject to altered rates of skin penetration and diffusion, resulting in up to 58% reduction of metabolites recovered from basal culture medium. The results indicate the reason for this altered behavior to be a microbially induced strengthening of the epidermal barrier. Concomitantly, colonized models showed decreased formation and penetration of the ultimate carcinogen B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), leading, in consequence, to fewer BPDE-DNA adducts being formed. Befittingly, transcript and expression levels of key proteins for repairing environmentally induced DNA damage such as xeroderma pigmentosum complementation group C (XPC) were also found to be reduced in the commensal models, as was expression of B[a]P-associated cytochrome P450-dependent monooxygenases (CYPs). The results show that the microbiome can have significant effects on the toxicology of external chemical impacts. The respective effects rely on a complex interplay between microbial and host metabolism and microbe-host interactions, all of which cannot be adequately assessed using single-system studies. IMPORTANCE Exposure to xenobiotics has repeatedly been associated with adverse health effects. While the majority of reported cases relate to direct substance effects, there is increasing evidence that microbiome-dependent metabolism of xenobiotic substances likewise has direct adverse effects on the host. This can be due to microbial biotransformation of compounds, interaction between the microbiota and the host's endogenous detoxification enzymes, or altered xenobiotic bioavailability. However, there are hardly any studies addressing the complex interplay of such interactions in situ and less so in human test systems. Using a recently developed microbially competent three-dimensional (3D) skin model, we show here for the first time how commensal influence on skin physiology and gene transcription paradoxically modulates PAH toxicity.

Dataset Information

Changes of serum amino acid profiles by an epidermal growth factor receptor mutation and benzo[a]pyrene in mouse lung tumorigenesis.

Publications

Changes of serum amino acid profiles by an epidermal growth factor receptor mutation and benzo[<i>a</i>]pyrene in mouse lung tumorigenesis.

Similar Datasets

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