Transcriptomic and histopathology changes in rat lung after intratracheal instillation of polymers

The lung toxicity of inhalable polymer materials is normally carried out by evaluation of the histopathology responses of rat lungs to repeat, nose-only, exposures of an inhalable aerosol of material in a 13-wk subchronic repeat dose toxicity study. The introduction of transcriptomics into toxicology has allowed the comparison of histopathological responses in target organs, after exposure, with the "signature" of gene expression (Waters et al., 2003), characteristic of the pathology processes known to be involved in the response to inhaled particulates. The transcriptomic and histopathological changes have been examined in a dose response study of the rat lung to intratracheally administered acrylate polymer solutions at time points equivalent to those used in a 13-wk inhalation study with an additional 13-wk recovery period. The doses administered in the intratracheal study were equivalent to the total doses achieved in a comparable 13-wk inhalation study. The changes in gene expression were found to be dose dependent, as was the histopathology. The changes in regulation of the genes expressed were also consistent with the histopathological responses, such as acute and chronic inflammation, commonly observed with inhalation exposure of the rat lungs to polymers. Functional classification of the genes affected highlight changes in inflammatory and immune response combined with macrophage recruitment, as well as cell adhesion and matrix formation. This would suggest a degree of tissue remodeling and is consistent with the histopathology observed. With further confirmation of the consistency of this response, the use of a transcriptomic approach in toxicology may be valuable in defining "signature" markers for the acute and chronic inflammation induced by polymers, or other inhalables, deposited in the lung. Osteopontin, in particular, a gene implicated in granuloma formation during chronic tissue damage, was significantly upregulated at high levels of exposure to polymer.