Gene Expression Changes in the Rat Nasal Epithelium Following Formaldehyde Exposure

Formaldehyde, an important industrial chemical, is used for multiple commercial purposes throughout the industrialized world. This simple, one carbon aldehyde is a natural metabolite formed in cells throughput the body. However, it is also a rodent nasal carcinogen, when inhaled by rats every day for two-years at irritant concentrations. High tumor incidences occur at concentration of 10 ppm and above; no tumors are observed at concentrations below 6.0 ppm. The US Environmental Protection Agency (US EPA) is now (2007) conducting a risk assessment to try to evaluate possible cancer risks for much lower levels of human exposure. Sensitive methods are needed to evaluate tissue responses below those concentrations that are clearly irritant or carcinogenic. This microarray study was undertaken to evaluate the mode of action for nasal responses to inhaled formaldehyde in Fisher 344 rats over a range of exposure concentrations. The range of concentrations used spanned those at which virtually no tissue responses were observed (0.7 ppm) to those that represent the highest concentration in the cancer studies (15 ppm) that produced nasal tumors in half the exposed group of rats. The study identified doses at which there were no statistically significant changes in gene expression; intermediate doses with changes in a small number of genes not easily grouped by function; and then concentrations where changes were consistent with irritation and cell stress responses. Keywords: time course, dose response, gene expression Eight week old male F344/NCrl rats were exposed to formaldehyde through either instillation or inhalation. For animals exposed via instillation, 40 ul per nostril of 400 mM formaldehyde was instilled intranasally. Vehicle control animals were instilled with 40 ul per nostril of distilled water. All animals exposed via instillation were sacrificed 6 hours post-exposure. For animals exposed via inhalation, whole-body exposures were performed at doses of 0, 0.7, 2, 6, and 15 ppm (6 hours per day, 5 days per week). Inhalation animals were sacrified at 6 hours, 24 hours, 5 days, and 19 days following initiation of exposure except for the 15 ppm concentration which was sacrificed at only the 6 hour time point. Following sacrifice, tissue from the Level II region of the nose was dissected and digested with a mixture of proteases to remove the epithelial cells. The epithelial cells scquired from this section of the nose consisted primarily of transitional epithelium with some respiratory epithelium. Microarray analysis was performed on the epithelial cells.