Efremenko A Y, Campbell J L, Dodd D E, Oller A R, Clewell H J
The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, North Carolina, 27709.
ScitoVation, 6 Davis Drive, Research Triangle Park, North Carolina, 27709.
Environ Mol Mutagen. 2017 Oct;58(8):607-618. doi: 10.1002/em.22139. Epub 2017 Sep 1.
While insoluble nickel subsulfide (Ni S ) was carcinogenic in the lung in a 2-year rat bioassay, soluble nickel sulfate hexahydrate (NiSO 6H 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 Ni S study have been reported previously; this paper reports the results for NiSO and provides a comparative analysis. The cellular responses to NiSO were highly similar to those previously reported for Ni S , 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 NiSO and particulate Ni S . Evaluation of the genomic concentration-responses for the two compounds suggests that the highest inhaled concentration in the tumor bioassay for NiSO , which was limited by toxicity, may not have achieved the Ni concentrations at which tumors were observed in the Ni S bioassay. However, several key differences in the immune responses to NiSO and Ni S were identified that may result from the differential intracellular disposition of Ni from NiSO entering the cell as an ion rather than as a slowly soluble Ni S particle. These differences may also contribute to the observation of tumors in the bioassay for Ni S but not NiSO . 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.
在一项为期两年的大鼠生物测定中，不溶性硫化镍（NiS）可导致肺部致癌，而可溶性六水合硫酸镍（NiSO₄·6H₂O）则不会。为了研究对这两种镍化合物的细胞反应差异是否可能是它们不同活性的基础，我们进行了平行研究，以确定在Fischer 344大鼠吸入这两种化合物1周和4周（每天6小时，每周5天）后，显微解剖的肺远端气道细胞中的基因表达变化。关于NiS的研究结果此前已报道；本文报告了NiSO₄的研究结果并提供了对比分析。对NiSO₄的细胞反应与之前报道的NiS的反应高度相似，并且鉴定出一组基因，其表达可用作生物标志物，以比较来自体外或体内研究的可溶性NiSO₄和颗粒状NiS的细胞镍效应。对这两种化合物的基因组浓度反应评估表明，在肿瘤生物测定中，受毒性限制的NiSO₄的最高吸入浓度可能未达到在NiS生物测定中观察到肿瘤的镍浓度。然而，确定了对NiSO₄和NiS的免疫反应存在几个关键差异，这可能是由于NiSO₄中的Ni以离子形式而非缓慢溶解的NiS颗粒形式进入细胞，导致细胞内分布不同所致。这些差异也可能导致在NiS的生物测定中观察到肿瘤，而在NiSO₄的生物测定中未观察到。《环境与分子突变》58:607 - 618，2017年。© 2017作者。《环境与分子突变》由Wiley Periodicals, Inc.代表环境诱变学会出版。
