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Toxicity, DNA Binding, and Cell Proliferation in Male F344 Rats following Short-term Gavage Exposures to Trans-2-Hexenal

¹ Curriculum in Toxicology and
² Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina, USA and
³ Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Correspondence: Address correspondence to: Dr. James A. Swenberg, Michael Hooker Research Center, University of North Carolina, Chapel Hill, NC 27599; e-mail: james_swenberg{at}unc.edu.

Hexenal is a genotoxic compound to which humans are exposed daily through the consumption of foods and beverages. The present studies were conducted to examine the relationships between the dose-responses of trans-2-hexenal-induced toxicity, DNA adduct formation, and cell proliferation. Male F344 rats were exposed by gavage to single doses of up to 500 mg/kg and killed 1, 2, or 4 days after dosing or were exposed to repeat doses of up to 100 mg/kg once daily for 5 days or 5 days per week for 4 weeks and killed 1 day after the end of the dosing period. Histologically, the primary observations were necroulcerative lesions, inflammation, and hyperplasia in the forestomach and inflammation in the glandular stomach. Hexenal-derived DNA adduct formation and cell proliferation were induced in the forestomach at doses of hexenal that also induced gastric toxicity; DNA adducts were not observed in the glandular stomach. These findings suggest that the toxicity of hexenal was limited to the site of contact (stomach) and that the observed DNA adduct formation and cell proliferation occurred in the setting of severe tissue damage.

Key Words: Hexenal • rat • forestomach • DNA adduct • mass spectrometry • proliferating cell nuclear antigen

Abbreviations: ALDH, aldehyde dehydrogenase • AR, aldose reductase • AS, analyte standard • CFE, Carworth Farm Strain E • CFW, Carworth Farm Swiss Webster • ctDNA, calf thymus DNA • DAB, 3 3’-diaminobenzidine • EDTA, ethylenediaminetetracetic acid • GSH, glutathione • GST, glutathione-S-transferase • Hexenal, trans-2-hexenal • H&E, hematoxylin and eosin • Hex-PdG, pair of diastereomeric exocyclic 1 N²-propanodeoxyguanosine adducts • HPLC, high performance liquid chromatography • ICR, Institute of Cancer Research • i.p., intraperitoneal • LC MS MS, liquid chromatography tandem mass spectrometry • NMR, nuclear magnetic resonance • NTP, National Toxicology Program • fmol, femtomol (10^–15 mol) • PCNA, proliferating cell nuclear antigen

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