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Comparative DNA damage and transcriptomic effects of engineered nanoparticles in human lung cells in vitro
Citation:
Nelson, G., S. Thai, C. Jones, A. Barbee, M. Killius, AND J. Ross. Comparative DNA damage and transcriptomic effects of engineered nanoparticles in human lung cells in vitro. 2016 Annual Meeting AACR, New Orleans, LA, April 16 - 20, 2016.
Impact/Purpose:
This work examines the ability of engineered nanomaterials to induce changes in gene expression and responses in a variety of short term assays when human respiratory cells are exposed in vitro. By standardizing the treatment conditions and examining the responses across a range of concentrations, inferences can be drawn about the relative abilities of these nanomaterials to induce a variety of types of reactive oxygen species and their biological sequelae. By linking DNA damage measured by multiple endpoints with assessments of oxidative stress and activation of stress response pathways, putative molecular initiating events in an oxidative stress adverse outcome pathway have been identified. Correlation of these cellular responses with chemical/physical properties of nanomaterials will allow for improved prediction of possible hazard for new nanomaterials for which only chemical/physical data are available.
Description:
A series of six titanium dioxide and two cerium oxide engineered nanomaterials were assessed for their ability to induce cytotoxicity, reactive oxygen species (ROS), various types of DNA damage, and transcriptional changes in human respiratory BEAS-2B cells exposed in vitro at several concentrations for 72 hours. Only limited cytotoxicity was observed at concentrations up to 300 µg/ml for all of the nanomaterials. Small increases in 8-oxo-deoxyguanosine were induced by some of the nanomaterials, but did not achieve statistical significance. No increases in ethenoadenosine or ethenocytidine were detected by ELISA assays for any of the tested nanomaterials. Several of the nanomaterials exhibited concentration related increases in levels of apurinic/apyrimidinic sites, endogenous DNA adducts measured by 32P-postlabeling, lipid peroxidation, and ROS. Consistent with these findings, several of the nanomaterials also affected expression of genes involved in p53, ATM, and mismatch repair pathways. Integrin signaling pathways were also altered by a majority of the nanomaterials tested. There was general agreement between activity in DNA damage assays and extent of pathway transcriptional alteration. One out of the cerium oxide nanomaterials tested did not induce a high enough incidence of differentially expressed genes relative to controls to allow analysis at the pathway level, and also elicited the lowest response in multiple DNA damage assays. Taken together, these data are consistent with the contribution of DNA damage induced by reactive oxygen species as mediators of potentially adverse biological effects following exposure to engineered titanium and cerium oxide nanomaterials, and suggests the utility of short term in vitro tests to predict relative potencies of these particles.This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.