Use of Neural Models of Proliferation and Neurite Outgrowth to Screen Environmental Chemicals in the ToxCast Phase I Library

Abstract

Abstract The U.S. Environmental Protection Agency's ToxCast program aims to develop rapid and cost-effective toxicity testing approaches. As part of this effort, we screened the ToxCast Phase I library of 309 chemicals using previously developed and optimized high-content imaging and analysis assays for proliferation in human ReNcell CX neuroprogenitor cells and neurite outgrowth in PC12 cells. Cytotoxicity was determined concurrently in both models. For the initial screening, cells were exposed in triplicate to chemicals at 40 μM for 24 (proliferation) or 96 hr (neurite outgrowth). Chemicals were deemed active if effects on any endpoint were >3×the standard deviation of control means. A total of 130/309 chemicals (42.1%) altered at least one of the four endpoints examined. In ReNcell CX cells, 126 (41%) of chemicals were active, and 46 (15%) were active in PC12 cells. In ReNcell CX cells, 63 chemicals selectively inhibited proliferation. In PC12 cells, only four chemicals (methyl isothiocyanate, phosalon...