ALTERED GENE EXPRESSION PROFILES OF RAT LUNG IN RESPONSE TO AN EMISSION PARTICULATE AND ITS METAL CONSTITUENTS

Abstract

Comprehensive and systematic approaches are needed to understand the molecular basis for the health effects of particulate matter (PM) reported in epidemiological studies. Due to the complex nature of the pollutant and the altered physiological conditions of predisposed populations, it has been difficult to establish a direct cause and effect relationship. A high-throughput technology such as gene expression profiling may be useful in identifying molecular networks implicated in the health effects of PM and its causative constituents. Differential gene expression profiles derived for rat lungs exposed to PM and its constituent metals using a custom rat cardiopulmonary cDNA array are presented here. This array consists of 84 cardiopulmonary-related genes representing various biological functions such as lung injury/inflammation, repair/remodeling, structural and matrix alterations, and vascular contractility, as well as six expressed sequence tags (ESTs). The cDNA array was hybridized with 32 P-labeled cDNA generated from rat lung RNA. Total lung RNA was isolated from male Sprague-Dawley rats at 3 and 24 h following intratracheal instillation of either saline, residual oil fly ash (ROFA; 3.3 mg/kg), or its most toxic metallic constituents, nickel (NiSO 4 ; 3.3 mmol/kg) and vanadium (VSO 4 ; 5.7 mmol/kg). Metal concentrations reflected the levels present in one ROFA instillate. Densitometric scans of the array blots indicated ROFA- and metal-specific increased expression (1.5 to 3-fold) of stress response, inflammatory, and repair-related genes, and also genes involved in vascular contractility and thrombogenic activity. Expression of multiple cytokines in ROFA exposed rat lung compared to Ni and V suggest the role and importance of understanding constituent interactions in PM toxicity. Expression profiling using genomic approaches will aid in our understanding of toxicant-specific altered molecular pathways in lung injury and pathogenesis.