Hypoxia Response: A Model Toxicity Pathway for High-Throughput Screening

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Abstract
The identification of toxicity pathways associated with known adverse health effects combined with engineered cellular assays that measure perturbations of these pathways is the keystone to the successful implementation of the recently formulated National Research Council (2007) report, Toxicity Testing in the 21st Century: A Vision and a Strategy. While the toxicology community probes biological space to define the edges of what may be confidently considered “toxicity pathways,” some well-characterized cellular signaling pathways will clearly fall within any reasonable definition of the term and represent first-tier candidates for immediate testing. Hypoxia response, like several of the toxicity pathway examples cited in the NRC report such as DNA damage response and Nrf2-mediated antioxidant response, is a key cellular stress response pathway that enables a cell to combat a variety of stressors. Although, there is a long-standing debate as to whether adaptive response such as hypoxia can be considered “adverse effects,” and while a imminent resolution is unlikely, these cell autonomous adaptive responses should be regarded as reflecting “perturbation” brought on by toxicant exposure that may portend dose-related adverse effects (reviewed by Simmons et al., in press). It is in this vein that a more judicious use of assays that measure adaptive biology can and should be included in strategies to identify and characterize toxic chemicals as exemplified in the paper by Xia et al. in this issue of Toxicological Sciences.