Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse.
Chem Res Toxicol
; 32(5): 887-898, 2019 05 20.
Article
em En
| MEDLINE
| ID: mdl-30990016
ABSTRACT
Metabolism of 1,3-butadiene, a known human and rodent carcinogen, results in formation of reactive epoxides, a key event in its carcinogenicity. Although mice exposed to 1,3-butadiene present DNA adducts in all tested tissues, carcinogenicity is limited to liver, lung, and lymphoid tissues. Previous studies demonstrated that strain- and tissue-specific epigenetic effects in response to 1,3-butadiene exposure may influence susceptibly to DNA damage and serve as a potential mechanism of tissue-specific carcinogenicity. This study aimed to investigate interindividual variability in the effects of 1,3-butadiene using a population-based mouse model. Male mice from 20 Collaborative Cross strains were exposed to 0 or 635 ppm 1,3-butadiene by inhalation (6 h/day, 5 days/week) for 2 weeks. We evaluated DNA damage and epigenetic effects in target (lung and liver) and nontarget (kidney) tissues of 1,3-butadiene-induced carcinogenesis. DNA damage was assessed by measuring N-7-(2,3,4-trihydroxybut-1-yl)-guanine (THB-Gua) adducts. To investigate global histone modification alterations, we evaluated the trimethylation and acetylation of histones H3 and H4 across tissues. Changes in global cytosine DNA methylation were evaluated from the levels of methylation of LINE-1 and SINE B1 retrotransposons. We quantified the degree of variation across strains, deriving a chemical-specific human variability factor to address population variability in carcinogenic risk, which is largely ignored in current cancer risk assessment practice. Quantitative trait locus mapping identified four candidate genes related to chromatin remodeling whose variation was associated with interstrain susceptibility. Overall, this study uses 1,3-butadiene to demonstrate how the Collaborative Cross mouse population can be used to identify the mechanisms for and quantify the degree of interindividual variability in tissue-specific effects that are relevant to chemically induced carcinogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Butadienos
/
Adutos de DNA
/
Epigênese Genética
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Chem Res Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos