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

Abstract:

OBJECTIVE:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. METHODS: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 0.60 mg/m(3) (0.03, 0.06, 0.11, and 0.44 mgNi/m(3)) for one and four weeks (6h/day, 5 days/week). RESULTS: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 1 week to up-regulation at 4 weeks. CONCLUSIONS: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 0.026 mgNi/m(3), for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 μgNi/g lung, for immune/inflammatory signaling. IMPLICATIONS:These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.

journal_name

Toxicol Appl Pharmacol

authors

Efremenko AY,Campbell JL Jr,Dodd DE,Oller AR,Clewell HJ 3rd

doi

10.1016/j.taap.2014.06.007

subject

Has Abstract

pub_date

2014-09-15 00:00:00

pages

441-454

issue

3

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(14)00230-0

journal_volume

279

pub_type

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