Blood Gene Expression Profiling Detects Silica Exposure and Toxicity

Abstract

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.

A mechanistic review of silica-induced inhalation toxicity

“…Elevated levels of macrophage inflammatory protein (MIP)-2 [a potent chemokine for PMN (Wolpe et al, 1989)] have been found in BALF of rats following a 5-day inhalation exposure to a-quartz at 15 mg/m 3 , but they returned to control level before they increased progressively later (Sellamuthu et al, 2011). In relation to this, macrophages, monocytes and dendritic cells (DCs) of different origins exposed to a-quartz in vitro have been demonstrated to enhance mRNA expression or protein production of IL-8 [a potent chemokine for PMN (Allen & Kurdowska, 2014)] (Xu et al, 2003) and MIP-2 (Rao et al, 2004;Sayes et al, 2007), although Zeidler et al (2003) failed to demonstrate enhanced MIP-2 production in murine bronchoalveolar lavage cells exposed to a-quartz.…”

Evaluation of Pulmonary Toxicity of Zinc Oxide Nanoparticles Following Inhalation and Intratracheal Instillation

“…However, it is also important to examine chronic responses, such as persistent inflammation. There are reports [10,11] that exposure to crystalline silica, a material known to have high toxicity, induced the onset of pulmonary inflammation after a certain observation time and more severe inflammation in the chronic phase. Considering the pulmonary toxicity of nanomaterials, it is important to evaluate the endpoints, such as inflammation and fibrosis, not only in the acute but also in the chronic phase.…”

Computer-automated silica aerosol generator and animal inhalation exposure system

“…(8) The system required a minimum of operator intervention over an exposure period. Following testing, this method for exposing small animals to various constant concentrations of SiO2 has proven to be very successful for researchers at NIOSH (Sellamuthu et al, 2011(Sellamuthu et al, , 2012. This exposure system was developed for crystalline silica particles, however the system would likely work with a wide variety of dry particles.…”

“…Research is being conducted which is attempting to accurately predict the outcome of occupational exposure to silica at early stages. For example, a hypothesis is being tested whether a blood gene expression profile can be used as a noninvasive marker capable of predicting organ toxicity in preclinical stages in workers who have occupational exposure risk to airborne silica (Sellamuthu et al, 2011(Sellamuthu et al, , 2012. To aid in this type of research, an automated system that could aerosolize, disperse and carefully control the airborne silica powder within an inhalation exposure chamber was developed.…”