Blood gene expression profiling was investigated as a minimally invasive surrogate approach to detect silica exposure and resulting pulmonary toxicity. Rats were exposed by inhalation to crystalline silica (15 mg/m³, 6 h/day, 5 days), and pulmonary damage and blood gene expression profiles were determined after latency periods (0-16 weeks). Silica exposure resulted in pulmonary toxicity as evidenced by histological and biochemical changes in the lungs. The number of significantly differentially expressed genes in the blood, identified by microarray analysis, correlated with the severity of silica-induced pulmonary toxicity. Functional analysis of the differentially expressed genes identified activation of inflammatory response as the major biological signal. Induction of pulmonary inflammation, as suggested by the blood gene expression data, was supported by significant increases in the number of macrophages and infiltrating neutrophils as well as the activity of pro-inflammatory chemokines observed in the lungs of the silica-exposed rats. A gene expression signature developed using the blood gene expression data predicted the exposure of rats to lower, minimally toxic and nontoxic concentrations of silica. Taken together, our findings suggest the potential application of peripheral blood gene expression profiling as a minimally invasive surrogate approach to detect pulmonary toxicity induced by silica in the rat. However, further research is required to determine the potential application of our findings specifically to monitor human exposure to silica and the resulting pulmonary effects.

The inhalation of engineered nanoparticles stimulates the development of atherosclerosis and impairs vascular function. However, the cardiac effects of inhaled engineered nanoparticles are unknown. Here, we investigate the effects of ultrafine titanium dioxide (UFTiO(2)) on the heart, and we define the possible mechanisms underlying the measured effects. Pulmonary exposure of rats to UFTiO(2) increased the phosphorylation levels of p38 mitogen-activated protein kinase and cardiac troponin I, but not Akt, in the heart and substance P synthesis in nodose ganglia. Circulatory levels of pro-inflammatory cytokines, and blood cell counts and differentials were not significantly changed after pulmonary exposure. Separately, the incubation of cardiac myocytes isolated from naïve adult rat hearts in vitro with UFTiO(2) did not alter the phosphorylation status of the same cardiac proteins. In conclusion, the inhalation of UFTiO(2) enhanced the phosphorylation levels of cardiac proteins. Such responses are likely independent of systemic inflammation, but may involve a lung-neuron-regulated pathway.