# Metabolic Mechanisms of Naphthalene Toxicity in Lung

> **NIH ES R01** · UNIVERSITY OF ARIZONA · 2026 · $664,123

## Abstract

Naphthalene (NA) is a ubiquitous and highly abundant pollutant found in vehicle exhaust, fossil fuels and
wildfire smoke. NA causes nasal and lung toxicity, including tumors, in rats and mice, respectively, and is a
possible human carcinogen. The mechanism of NA carcinogenicity, which may involve both genotoxic and non-
genotoxic events, is not clear and may involve several reactive NA metabolites. A prerequisite for NA toxicity is
bioactivation by cytochrome P450 (CYP) to form NA-epoxide (NAO) which can undergo further metabolism in
the lung and liver to 1,2-naphthoquinone (1,2-NQ). Both NAO and 1,2-NQ can react with DNA. We have recently
uncovered a significant contribution of liver-generated NA metabolites to acute lung toxicity in vivo; identified
several NQ-DNA adducts in the mouse lung, liver, and blood following NA exposure and in blood samples from
human firefighters and lung biopsy samples of lung cancer patients; and gained novel insights on the
toxicokinetics of various NA metabolites. These exciting findings led to the current proposal, to test the novel
hypothesis that liver-generated reactive NA metabolites are transported to the lung where they contribute to NA's
cytotoxicity, genotoxicity, and carcinogenesis. We are well positioned to address this hypothesis due to the
genetically modified mouse models we have developed, the recent methodologic advances we have made in
metabolite and DNA adduct characterization, and the exposure systems we have in place to expose mice acutely
and/or chronically to NA vapor at defined doses. A series of mechanistic and translational studies will be carried
out in four Specific Aims that will 1) identify key metabolic events that control NA DNA adduct formation in the
lung, 2) determine whether serum albumin facilitates transport of liver-generated reactive NA metabolites to the
lung, 3) identify whether key metabolic events in the liver mediate NA-induced lung tumorigenesis in vivo, and
4) characterize profiles of NA 

## Key facts

- **NIH application ID:** 11240318
- **Project number:** 5R01ES020867-14
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Xinxin  Ding; Laura S Van Winkle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** ES
- **Fiscal year:** 2026
- **Award amount:** $664,123
- **Award type:** 5
- **Project period:** 2013-08-20T00:00:00 → 2029-11-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11240318

## Citation

> US National Institutes of Health, RePORTER application 11240318, Metabolic Mechanisms of Naphthalene Toxicity in Lung (5R01ES020867-14). Retrieved via AI Analytics 2026-05-19 from https://api.ai-analytics.org/grant/nih/11240318. Licensed CC0.

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