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Using high-content imaging data from ToxCast to analyze toxicological tipping points (TDS)
Citation:
Shah, I. Using high-content imaging data from ToxCast to analyze toxicological tipping points (TDS). Presented at US EPA’s Chemical Safety Research: Second ToxCast Data Summit, RTP, NC, September 29 - 30, 2014.
Impact/Purpose:
This work describes the application of ToxCast data and Virtual Tissues to estimate toxicological points of departure.
Description:
Translating results obtained from high-throughput screening to risk assessment is vital for reducing dependence on animal testing. We studied the effects of 976 chemicals (ToxCast Phase I and II) in HepG2 cells using high-content imaging (HCI) to measure dose and time-dependent perturbations in p53, JNK, oxidative stress, cytoskeleton, mitochondria, and cell cycle. A novel computational model was developed to describe the dynamic response of the system as cell-state trajectories based on multidimensional HCI datastreams. Cell-state trajectories produced by 10 concentrations (0.4 to 200 μM) of 967 chemicals showed resilience of the HepG2 system in many cases, however, we also found "tipping points" in system recovery. Further analysis of trajectories identified dose-dependent transitions, or critical points, in system recovery for 340/967 chemicals. The critical concentration was generally 5-times lower than the concentration that produced cell loss. We believe that HCI can be used to reconstruct cell state trajectories, and provide insight into adaptation and resilience for in vitro systems. With additional research, cellular tipping points could be used to define an in vitro point of departure (PoD) for risk-based prioritization of environmental chemicals.