PNNL

Abstract

The vast diversity of engineered nanoparticles (ENPs) under development is driving demand for new approaches for predictive toxicological and hazard analysis, placing increased importance on rapid in vitro (cellular) test systems for nanotoxicology. While the potential health effects of engineered nanomaterials in humans remain uncertain, evidence links exposure to nanoscale particulates from ambient and occupational sources with increased susceptibility to lung infections, including pneumonia. Here, we applied an in vitro assay amenable to high throughput to evaluate the effects of pretreatment with 16 different ENP types on the ability of macrophages to phagocytize Streptococcus pneumoniae, the leading cause of community-acquired pneumonia. Hierarchical clustering analysis of the results revealed three major classes of ENPs, ranging from metal oxide ENPs which induce macrophage cytotoxicity and robustly inhibit phagocytic function (e.g., CuO, CoO), to ENPs that had no detectable adverse effects (e.g. SiO2, TiO2). Importantly, some ENPs that lacked bioactivity by conventional cytotoxicity measures, (e.g., Fe3O4) were found to significantly suppress macrophage phagocytic function. Lung infection studies in mice using three ENPs, representing the low, medium and high toxic groups, showed excellent correspondence with in vitro predictions of their inhibitory effects on lung clearance/survival of S. pneumonia in vivo. Structure-activity modeling and gene expression analysis suggest that the potential of an ENP to enhance susceptibility to S. pneumoniae is driven by its propensity to induce oxidative stress and reprogram macrophage activation responses. Our results demonstrate the important concept that adverse biological consequences of nanomaterials may not always be directly mediated, but can be manifested by altering susceptibility to other common environmental exposures. The current study warrants careful consideration of these biological endpoints of susceptibility from both a mechanistic and hazard assessment framework for engineered nanoparticles.