Biomarkers of exposure and effect in human lymphoblastoid TK6 cells following [13C2]-acetaldehyde exposure

• Published in: Toxicological sciences Vol. 133; no. 1; pp. 1 - 12
• Main Authors: Moeller, Benjamin C, Recio, Leslie, Green, Amanda, Sun, Wei, Wright, Fred A, Bodnar, Wanda M, Swenberg, James A
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-05-2013
• Subjects: Acetaldehyde - toxicity; Aldehyde Dehydrogenase - genetics; Aldehyde Dehydrogenase, Mitochondrial; Carbon Isotopes; Cell Culture Techniques; Cell Line, Tumor; Cell Survival - drug effects; Chromatography, High Pressure Liquid; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - analysis; DNA Adducts - analysis; Dose-Response Relationship, Drug; Environmental Exposure - analysis; Flow Cytometry; Genotype; Humans; Micronuclei, Chromosome-Defective - chemically induced; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kft029

The dose-response relationship for biomarkers of exposure (N(2)-ethylidene-dG adducts) and effect (cell survival and micronucleus formation) was determined across 4.5 orders of magnitude (50nM-2mM) using [(13)C2]-acetaldehyde exposures to human lymphoblastoid TK6 cells for 12h. There was a clear increase in exogenous N (2)-ethylidene-dG formation at exposure concentrations ≥ 1µM, whereas the endogenous adducts remained nearly constant across all exposure concentrations, with an average of 3.0 adducts/10(7) dG. Exogenous adducts were lower than endogenous adducts at concentrations ≤ 10µM and were greater than endogenous adducts at concentrations ≥ 250µM. When the endogenous and exogenous adducts were summed together, statistically significant increases in total adduct formation over the endogenous background occurred at 50µM. Cell survival and micronucleus formation were monitored across the exposure range and statistically significant decreases in cell survival and increases in micronucleus formation occurred at ≥ 1000µM. This research supports the hypothesis that endogenously produced reactive species, including acetaldehyde, are always present and constitute the majority of the observed biological effects following very low exposures to exogenous acetaldehyde. These data can replace default assumptions of linear extrapolation to very low doses of exogenous acetaldehyde for risk prediction.