The July 2018 Editor's Choice article is "Assessment of a panel of cellular biomarkers and the kinetics of their induction in comparing genotoxic modes of action in HepG2 cells" (https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22197) by Benjamin Kopp, Morgane Dario, Daniel Zalko, and Marc Audebert.
Understanding the genotoxic mode of action is a critical aspect of cancer risk assessment, particularly for interpreting potential interactions between chemicals in mixtures. Genotoxicity refers to the ability of chemicals to damage the genetic material within a cell (i.e., DNA, RNA). Chemicals induce DNA damage through a variety of mechanisms, such as DNA adduct induction, and generate different types of damage. For example, clastogens induce DNA strand breaks and aneugens cause abnormalities in chromosome number. Kopp et al. investigated whether proteins that become phosphorylated as part of the cellular DNA damage signaling pathway could (alone or in combination) be used as biomarkers to distinguish different mechanisms of DNA damage.
Kopp et al. treated human HepG2 cells with ten chemicals that induce DNA damage by the mechanisms mentioned above, using a range of doses and exposures of different duration. Nine of the chemicals were clastogens that operate through topoisomerase inhibition, base modification, induction of a dNTP pool imbalance or spindle poisoning. An “in-cell” western technique was used to quantify eight phosphorylated proteins known to be induced as part of DNA damage response signaling. All nine tested clastogenic compounds showed a time- and concentration-dependent activation of the tested biomarkers. Although no specific biomarker signature of clastogenic mode of action was determined, a strong correlation between γH2AX and p-p53(S15) was observed for clastogens, but not for aneugens. Thus, this Editor’s Choice article combined systematic in vitro analysis of clastogens with the use of a high-throughput In-cell western technique and will be of interest to investigators evaluating the cancer risk posed by clastogens. Environ. Mol. Mutagen. 59:516-528, 2018. © Wiley Periodicals, Inc.