Gene expression microarray analysis of rat nasal tissue with time and dose following formaldehyde inhalation

Formaldehyde (FA), an endogenous cellular aldehyde, is a rat nasal carcinogen. In this study, concentration- and exposure-duration transitions in FA mode of action (MOA) were examined with pharmacokinetic (PK) modeling for tissue formaldehyde acetal (FAcetal) and glutathione (GSH) and with histopathology and gene expression studies for tissue responses in nasal epithelium from rats exposed to 0, 0.7, 2, 6, 10 or 15 ppm FA 6 hr/day for 1, 4 or 13 weeks. The study had two goals. The first goal was to develop a basic PK model to estimate various forms of tissue formaldehyde and tissue glutathione (GSH). The second goal was to compare histopathology and gene expression changes in nasal tissues caused by inhalation of FA with changes in tissue FAcetal and free GSH calculated from the PK model. Patterns of gene expression varied with concentration and with duration. At 0.7 and 2 ppm, sensitive response genes (SRGs) - associated with cellular stress, thiol transport/reduction, inflammation, and cell proliferation - were similarly upregulated at all exposure durations. At 6 ppm and greater, gene expression changes showed enrichment of pathways involved in cell cycle, DNA repair, and apoptosis processes. ERBB, EGFR, WNT, TGF-, Hedgehog, and Notch signaling were also enriched in differentially expressed genes. Benchmark doses (BMDs) for genes in significantly enriched pathways were lower at 13 weeks than at 1 or 4-week. The transcriptional and histological changes corresponded to PK model-predicted changes in free GSH at 0.7 and 2 ppm and in FAcetal at 6 ppm. DNA-replication stress, enhanced proliferation, metaplasia, and stem cell-niche activation appear to be associated with FA carcinogenesis at 6 ppm and above. Dose dependencies in MOA, the presence of high physiological FAcetal, and non-linear FAcetal/GSH tissue kinetics indicate that FA concentrations below 150 ppb (and probably any concentrations below irritant levels, i.e., ~ 1 ppm) would not increase cancer risks of inhaled FA in the nose or any other tissue. Closer examination of dose response relationships for endogenous compound toxicity could help guide biologically relevant approaches for chemical risk assessment.

72

Andersen ME, Clewell HJ 3rd, Bermudez E, Dodd DE, Willson GA, Campbell JL, Thomas RS