Acute exposure to dihydroxyacetone promotes genotoxicity and chromosomal instability in lung, cardiac, and liver cell models

• Published in: Toxicological sciences Vol. 201; no. 1; pp. 85 - 102
• Main Authors: Hernandez, Arlet, Hedlich-Dwyer, Jenna, Hussain, Saddam, Levi, Hailey, Sonavane, Manoj, Suzuki, Tetsuya, Kamiya, Hiroyuki, Gassman, Natalie R
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2024
• Subjects: A549 Cells; Cell Line; Chromosomal Instability - drug effects; Dihydroxyacetone - toxicity; DNA Adducts; DNA Damage; Dose-Response Relationship, Drug; Humans; Liver - drug effects; Liver - metabolism; Liver - pathology; Lung - drug effects; Lung - metabolism; Lung - pathology; Mutagenicity Tests; Mutagens - toxicity; dihydroxyacetone; genotoxicity; DNA adducts; e-cigarettes; cytotoxicity
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfae075

Abstract Inhalation exposures to dihydroxyacetone (DHA) occur through spray tanning and e-cigarette aerosols. Several studies in skin models have demonstrated that millimolar doses of DHA are cytotoxic, yet the genotoxicity was unclear. We examined the genotoxicity of DHA in cell models relevant to inhalation exposures. Human bronchial epithelial cells BEAS-2B, lung carcinoma cells A549, cardiomyocyte Ac16, and hepatocellular carcinoma HepG3 were exposed to DHA, and low millimolar doses of DHA were cytotoxic. IC90 DHA doses induced cell cycle arrest in all cells except the Ac16. We examined DHA’s genotoxicity using strand break markers, DNA adduct detection by Repair Assisted Damage Detection (RADD), metaphase spreads, and a forward mutation assay for mutagenesis. Similar to results for skin, DHA did not induce significant levels of strand breaks. However, RADD revealed DNA adducts were induced 24 h after DHA exposure, with BEAS-2B and Ac16 showing oxidative lesions and A549 and HepG3 showing crosslink-type lesions. Yet, only low levels of reactive oxygen species or advanced glycation end products were detected after DHA exposure. Metaphase spreads revealed significant increases in chromosomal aberrations in the BEAS-2B and HepG3 with corresponding changes in ploidy. Finally, we confirmed the mutagenesis observed using the supF reporter plasmid. DHA increased the mutation frequency, consistent with methylmethane sulfonate, a mutagen and clastogen. These data demonstrate DHA is a clastogen, inducing cell-specific genotoxicity and chromosomal instability. The specific genotoxicity measured in the BEAS-2B in this study suggests that inhalation exposures pose health risks to vapers, requiring further investigation.