Expression data for Male Fischer 344 rat exposed to 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 F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per 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 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 µg Ni/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.本数据集旨在通过探究吸入暴露后靶细胞的基因表达（gene expression）变化，解析三硫化二镍（Ni3S2）的肺癌致癌作用模式。研究以Fischer F344大鼠的显微切割（micro-dissected）肺支气管肺泡细胞为对象，将其暴露于浓度分别为0.0、0.04、0.08、0.15及0.60 mg/m³（对应镍浓度为0.03、0.06、0.11及0.44 mg Ni/m³）的三硫化二镍环境中，暴露时长设为1周与4周（每日6小时，每周5天），并检测其基因表达变化。 **结果**：支气管肺泡灌洗液（broncho-alveolar lavage fluid）检测与肺组织病理学分析仅在两个最高暴露浓度下观察到炎症证据，该浓度范围与两年生物测定中所用的暴露浓度一致。暴露1周与4周后，具有统计学意义的上调与下调基因数量均显著下降，提示机体产生了适应性反应。两个时间点下的细胞信号通路富集分析结果均主要反映了毒性应激反应，涵盖炎症信号与增殖信号通路。尽管增殖信号在两个时间点均呈上调趋势，但部分炎症信号的表达趋势发生反转：1周时为下调，4周时转为上调。 **结论**：本研究结果支持三硫化二镍的致癌作用模式为：通过慢性毒性、炎症反应与细胞增殖异常引发复制错误，而非直接的遗传毒性（genotoxicity）。基准剂量（Benchmark Dose, BMD）分析显示，针对凋亡/存活信号通路的最低通路转录基准剂量暴露浓度为0.026 mg Ni/m³。若以肺组织镍浓度为计算基准，则针对免疫/炎症信号通路的最低通路BMD为0.64 µg Ni/g肺组织。 **研究意义**：该保守性较强的基准剂量可用于推导三硫化二镍毒性与致癌性非线性风险评估中的风险起始点。