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Nanomaterial (NM) bioactivity profiling by ToxCast high-throughput screening (HTS)
Citation:
WANG, A., E. L. BERG, M. POLOKOFF, J. YANG, D. REIF, N. KLEINSTREUER, S. MARINAKOS, A. BADIREDDY, S. GANGWAL, C. W. MATSON, MARK R. WIESNER, AND K. A. HOUCK. Nanomaterial (NM) bioactivity profiling by ToxCast high-throughput screening (HTS) . Presented at The Society of Toxicology (SOT) 51st Annual Meeting and ToxExpo 2012, Moscone Convention Center, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Comparing our data to BioMAP® reference profiles suggested targets that weren’t directly measured, e.g. nano-Ag had a similar profile as ciclopirox, a N+ K+ ATPase inhibitor, and nano-TiO2 to Paclitaxel, a microtubule stabilizer interfering with mitosis. The interactions (Ag/N+ K+ ATPase; nano-TiO2/microtubules) were previously reported in the literature. In short, NM cores are critical to bioactivities and NM effects are often similar to their ions’. Moreover, in vitro HTS allows examination of molecular targets and pathways affected by NMs.
Description:
Rapidly increasing numbers of new NMs and their uses demand efficient tests of NM bioactivity for safety assessment. The EPA’s ToxCast program uses HTS assays to prioritize for targeted testing, identify biological pathways affected, and aid in linking NM properties and potential in vivo effects. NMs (Au, Ag, CeO2, CNT, CuO, TiO2, SiO2, or ZnO core) and their ion and micro counterparts were tested for cytotoxicity in various cell types, for transcription factor (TF) activation in HepG2 cells, and by protein expression in 8 BioMAP® human primary cell systems. Tested concentrations were from below the in vitro equivalents of the MPPD model–predicted lung retention (mass/surface area) after 24h exposure to reported NM concentrations in air to about the equivalent of 45yr exposure. Assay/cell sensitivities to cytotoxicity varied, but the cytotoxicity rank order was the same in various assays. Materials with the same core composition had similar bioactivity profiles, particularly NMs and their corresponding ions, except the nano-ZnO TF profile. Principle component analysis showed TF and protein profiles were mainly affected by core composition and not by size. MetaCore analysis showed NMs affected multiple pathways, including cellular stress and immune function regulation. Comparing our data to BioMAP® reference profiles suggested targets that weren’t directly measured, e.g. nano-Ag had a similar profile as ciclopirox, a N+ K+ ATPase inhibitor, and nano-TiO2 to Paclitaxel, a microtubule stabilizer interfering with mitosis. The interactions (Ag/N+ K+ ATPase; nano-TiO2/microtubules) were previously reported in the literature. In short, NM cores are critical to bioactivities and NM effects are often similar to their ions’. Moreover, in vitro HTS allows examination of molecular targets and pathways affected by NMs. This abstract does not necessarily reflect US EPA policy