Using Transcriptomics to Evaluate Thresholds in Genotoxicity Dose–Response

Abstract

Several genotoxic chemicals have been reported to produce threshold-shaped dose–response curves for mutation and genotoxicity assays, both in vivo and in vitro, challenging the current default practice for risk assessment of genotoxic chemicals, which assumes a linear dose–response below the lowest tested dose. Statistical methods cannot determine whether a biological threshold exists with sufficient confidence to overturn this assumption of linearity. Indeed, to truly define the shape of the dose–response curves, we must look to the underlying biology and develop targeted experiments to identify and measure the key processes governing the response of the cell to DNA damage. This chapter describes a series of studies aimed at defining the key transcriptional responses. Two approaches were taken to evaluate transcriptional responses preventing micronucleus induction: (1) comparison of gene signatures for several prototype compounds at a single chemical dose that led to a similar activation of the p53-DNA damage pathway (i.e. 1.5-fold increase in total p53); and (2) evaluation of a subset of chemicals with in-depth dose–response studies. The goal of these efforts was to determine the transcriptional pathways responsible for maintaining homeostasis at low levels of DNA damage, i.e., the biological underpinning of threshold-shaped dose–response curves for mutagenicity.