title: 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.
  
  
  CONCLUSIONS
  These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
authors: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA. Electronic address: aefremenko@thehamner.org.
authors: A Y
authors: AY
authors: Efremenko
authors: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors: J L
authors: JL
authors: Campbell
authors: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors: D E
authors: DE
authors: Dodd
authors: NiPERA, Inc., 2525 Meridian Parkway, Suite 240, Durham, NC 27713, USA.
authors: A R
authors: AR
authors: Oller
authors: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors: H J
authors: HJ
authors: Clewell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019985:Benchmarking; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D019570:Inhalation Exposure; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D009153:Mutagens; D009532:Nickel / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002273:Carcinogens; D009153:Mutagens; D009532:Nickel; C017557:nickel subsulfide
keywords: Carcinogenicity; Gene expression; Inhalation; Nickel subsulfide