title: Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage.
abstract: Formaldehyde is not only a widely used chemical with well-known carcinogenicity but is also a normal metabolite of living cells. It thus poses unique challenges for understanding risks associated with exposure. N(2-)hydroxymethyl-dG (N(2)-HOMe-dG) is the main formaldehyde-induced DNA mono-adduct, which together with DNA-protein crosslinks (DPCs) and toxicity-induced cell proliferation, play important roles in a mutagenic mode of action for cancer. In this study, N(2)-HOMe-dG was shown to be an excellent biomarker for direct adduction of formaldehyde to DNA and the hydrolysis of DPCs. The use of inhaled [(13)CD2]-formaldehyde exposures of rats and primates coupled with ultrasensitive nano ultra performance liquid chromatography-tandem mass spectrometry permitted accurate determinations of endogenous and exogenous formaldehyde DNA damage. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact. The amounts of exogenous adducts were remarkably lower than those of endogenous adducts in exposed nasal epithelium. Moreover, exogenous adducts accumulated in rat nasal epithelium over the 28-days exposure to reach steady-state concentrations, followed by elimination with a half-life (t1/2) of 7.1 days. Additionally, we examined artifact formation during DNA preparation to ensure the accuracy of nonlabeled N(2)-HOMe-dG measurements. These novel findings provide critical new data for understanding major issues identified by the National Research Council Review of the 2010 Environmental Protection Agency's Draft Integrated Risk Information System Formaldehyde Risk Assessment. They support a data-driven need for reflection on whether risks have been overestimated for inhaled formaldehyde, whereas underappreciating endogenous formaldehyde as the primary source of exposure that results in bone marrow toxicity and leukemia in susceptible humans and rodents deficient in DNA repair.
authors.affiliation: *Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Rui
authors.initials: R
authors.lastname: Yu
authors.affiliation: *Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Lai
authors.affiliation: *Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Hadley J
authors.initials: HJ
authors.lastname: Hartwell
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108; and.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Moeller
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108; and.
authors.forename: Melanie
authors.initials: M
authors.lastname: Doyle-Eisele
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108; and.
authors.forename: Dean
authors.initials: D
authors.lastname: Kracko
authors.affiliation: *Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Bodnar
authors.affiliation: *Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599, TBS Associates, 7500 Rainwater Road, Raleigh, North Carolina 27615.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Starr
authors.affiliation: *Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599, jswenber@email.unc.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005557:Formaldehyde / Q000633:toxicity*; D006801:Humans; D006868:Hydrolysis; D051381:Rats; D053719:Tandem Mass Spectrometry
chemical_list: D005557:Formaldehyde; D004247:DNA
keywords: DNA monoadducts; DNA-protein crosslinks; accumulation; artifacts; distribution; endogenous; exogenous; formaldehyde; half-life; nano liquid chromatography-tandem mass spectrometry; steady state