Formation of hydroxymethyl DNA adducts in rats orally exposed to stable isotope labeled methanol

Kun Lu, Husamettin Gul, Patricia B. Upton, Benjamin Moeller, James A. Swenberg

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Methanol is a large volume industrial chemical and widely used solvent and fuel additive. Methanol's well known toxicity and use in a wide spectrum of applications has raised long-standing environmental issues over its safety, including its carcinogenicity. Methanol has not been listed as a carcinogen by any regulatory agency; however, there are debates about its carcinogenic potential. Formaldehyde, a metabolite of methanol, has been proposed to be responsible for the carcinogenesis of methanol. Formaldehyde is a known carcinogen and actively targets DNA and protein, causing diverse DNA and protein damage. However, formaldehyde-induced DNA adducts arising from the metabolism of methanol have not been reported previously, largely due to the absence of suitable DNA biomarkers and the inability to differentiate what was due to methanol compared with the substantial background of endogenous formaldehyde. Recently, we developed a unique approach combining highly sensitive liquid chromatography-mass spectrometry methods and exposure to stable isotope labeled chemicals to simultaneously quantify formaldehyde-specific endogenous and exogenous DNA adducts. In this study, rats were exposed daily to 500 or 2000 mg/kg [ 13CD 4]-methanol by gavage for 5 days. Our data demonstrate that labeled formaldehyde arising from [ 13CD 4]-methanol induced hydroxymethyl DNA adducts in multiple tissues in a dose-dependent manner. The results also demonstrated that the number of exogenous DNA adducts was lower than the number of endogenous hydroxymethyl DNA adducts in all tissues of rats administered 500 mg/kg per day for 5 days, a lethal dose to humans, even after incorporating an average factor of 4 for reduced metabolism due to isotope effects of deuterium-labeled methanol into account.

Original languageEnglish (US)
Pages (from-to)28-38
Number of pages11
JournalToxicological Sciences
Volume126
Issue number1
DOIs
StatePublished - Mar 13 2012
Externally publishedYes

Fingerprint

DNA Adducts
Isotopes
Methanol
Rats
Formaldehyde
Metabolism
Carcinogens
DNA
Tissue
Fuel additives
Industrial chemicals
Deuterium
Liquid chromatography
Biomarkers
Metabolites
Liquid Chromatography
DNA Damage
Mass spectrometry
Toxicity
Mass Spectrometry

Keywords

  • DNA adducts
  • Formaldehyde
  • Genetic toxicology
  • Hydroxymethyl adducts
  • Mass spectrometry
  • Methanol

ASJC Scopus subject areas

  • Toxicology

Cite this

Formation of hydroxymethyl DNA adducts in rats orally exposed to stable isotope labeled methanol. / Lu, Kun; Gul, Husamettin; Upton, Patricia B.; Moeller, Benjamin; Swenberg, James A.

In: Toxicological Sciences, Vol. 126, No. 1, 13.03.2012, p. 28-38.

Research output: Contribution to journalArticle

Lu, Kun ; Gul, Husamettin ; Upton, Patricia B. ; Moeller, Benjamin ; Swenberg, James A. / Formation of hydroxymethyl DNA adducts in rats orally exposed to stable isotope labeled methanol. In: Toxicological Sciences. 2012 ; Vol. 126, No. 1. pp. 28-38.
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