Title: Naphthalene DNA adduct formation and tolerance in the lung

Abstract

Naphthalene (NA) is a respiratory toxicant and possible human carcinogen. NA is a ubiquitous combustion product and significant component of jet fuel. The National Toxicology Program found that NA forms tumors in two species, in rats (nose) and mice (lung). However, it has been argued that NA does not pose a cancer risk to humans because NA is bioactivated by cytochrome P450 monooxygenase enzymes that have very high efficiency in the lung tissue of rodents but low efficiency in the lung tissue of humans. It is thought that NA carcinogenesis in rodents is related to repeated cycles of lung epithelial injury and repair, an indirect mechanism. Repeated in vivo exposure to NA leads to development of tolerance, with the emergence of cells more resistant to NA insult. We tested the hypothesis that tolerance involves reduced susceptibility to the formation of NA-DNA adducts. NA-DNA adduct formation in tolerant mice was examined in individual, metabolically-active mouse airways exposed ex vivo to 250 μM ¹⁴C-NA. Ex vivo dosing was used since it had been done previously and the act of creating a radioactive aerosol of a potential carcinogen posed too many safety and regulatory obstacles. Following extensive rinsing to remove unbound ¹⁴C-NA, DNAmore » was extracted and ¹⁴C-NA-DNA adducts were quantified by accelerator mass spectrometry (AMS). The tolerant mice appeared to have slightly lower NA-DNA adduct levels than non-tolerant controls, but intra-group variations were large and the difference was statistically insignificant. It appears the tolerance may be more related to other mechanisms, such as NA-protein interactions in the airway, than DNA-adduct formation.« less

Authors:

Buchholz, Bruce A. ^[1]; Carratt, Sarah A. ^[2]; Kuhn, Edward A. ^[3]; Collette, Nicole M. ^[3]; Ding, Xinxin ^[4]; Van Winkle, Laura S. ^[2]

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+ Show Author Affiliations

1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Center for Accelerator Mass Spectrometry
2. Univ. of California, Davis, CA (United States). Center for Health and the Environment
3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Bioscience and Biotechnology Division
4. Univ. of Arizona, Tucson, AZ (United States). College of Pharmacy, Dept. of Pharmacology and Toxicology

Publication Date:

Fri Jul 13 00:00:00 EDT 2018

Research Org.:

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Org.:

USDOE National Nuclear Security Administration (NNSA)

OSTI Identifier:

1488795

Report Number(s):

LLNL-JRNL-741718
Journal ID: ISSN 0168-583X; 896334

Grant/Contract Number:  

AC52-07NA27344

Resource Type:

Accepted Manuscript

Journal Name:

Nuclear Instruments and Methods in Physics Research. Section B, Beam Interactions with Materials and Atoms

Additional Journal Information:

Journal Volume: 438; Journal Issue: C; Journal ID: ISSN 0168-583X

Publisher:

Elsevier

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; Naphthalene; DNA adducts; Carcinogen; Tolerance test