Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide

To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60mg/m3 (0.03, 0.06, 0.11, and 0.44mgNi/m3) for one and four weeks (6h/day, 5days/week). Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1week to up-regulation at 4weeks. These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026mgNi/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64μgNi/g lung, for immune/inflammatory signaling. These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity. •The mode of action for lung carcinogenicity of inhaled Ni3S2 was investigated in rats.•Gene expression changes were determined in micro-dissected lung tissue at 1–4weeks.•A non-genotoxic mode of action (toxicity, inflammation, proliferation) was supported.•Analyses of lung lavage fluid and histopathology provided complementary results.•Transcriptional benchmark doses could inform point of departure for risk assessment.