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

While insoluble nickel subsulfide (Ni₃ S₂ ) was carcinogenic in the lung in a 2-year rat bioassay, soluble nickel sulfate hexahydrate (NiSO_4* 6H₂ O) was not. To investigate whether differences in the cellular responses to these two nickel compounds could underlie their differential activities, we conducted parallel studies to determine the gene expression changes in micro-dissected lung distal airway cells from Fischer 344 rats following inhalation of the two compounds for one and four weeks (6 hr per day, 5 days per week). The results of the Ni₃ S₂ study have been reported previously; this paper reports the results for NiSO₄ and provides a comparative analysis. The cellular responses to NiSO₄ were highly similar to those previously reported for Ni₃ S₂ , and a set of genes was identified whose expression could be used as biomarkers for comparing cellular nickel effects from in vitro or in vivo studies with soluble NiSO₄ and particulate Ni₃ S₂ . Evaluation of the genomic concentration-responses for the two compounds suggests that the highest inhaled concentration in the tumor bioassay for NiSO₄ , which was limited by toxicity, may not have achieved the Ni concentrations at which tumors were observed in the Ni₃ S₂ bioassay. However, several key differences in the immune responses to NiSO₄ and Ni₃ S₂ were identified that may result from the differential intracellular disposition of Ni from NiSO₄ entering the cell as an ion rather than as a slowly soluble Ni₃ S₂ particle. These differences may also contribute to the observation of tumors in the bioassay for Ni₃ S₂ but not NiSO₄ . Environ. Mol. Mutagen. 58:607-618, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.