Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

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Ozone (O3) is an oxidant gas that can directly induce lung injury. Knowledge of the initial molecular events of the acute O3 response would be useful in developing biomarkers of exposure or response. Toward this goal, we exposed rats to toxic concentrations of O3 (2 and 5 ppm) for 2 hr and the molecular changes were assessed in lung tissue 2 hr postexposure using a rat cDNA expression array containing 588 characterized genes. Gene array analysis indicated differential expression in almost equal numbers of genes for the two exposure groups: 62 at 2 ppm and 57 at 5 ppm. Most of these genes were common to both exposure groups, suggesting common roles in the initial toxicity response. However, we also identified the induction of nine genes specific to 2-ppm (thyroid hormone-β receptor c-erb-A-β and glutathione reductase) or 5-ppm exposure groups (c-jun, induced nitric oxide synthase, macrophage inflammatory protein-2, and heat shock protein 27). Injury markers in bronchoalveolar lavage fluid (BALF) were used to assess immediate toxicity and inflammation in rats similarly exposed. At 2 ppm, injury was marked by significant increases in BALF total protein, N-acetylglucosaminidase, and lavageable ciliated cells. Because infiltration of neutrophils was observed only at the higher 5 ppm concentration, the distinctive genes suggested a potential amplification role for inflammation in the gene profile. Although the specific gene interactions remain unclear, this is the first report indicating a dose-dependent direct and immediate induction of gene expression that may be separate from those genes involved in inflammation after acute O3 exposure.

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.