McKenna I M, Gordon T, Chen L C, Anver M R, Waalkes M P
Laboratory of Comparative Carcinogenesis, National Cancer Institute, USA.
Toxicol Appl Pharmacol. 1998 Dec;153(2):169-78. doi: 10.1006/taap.1998.8399.
Chronic exposure to inhaled cadmium (Cd) has been shown to induce lung tumors in rats (Wistar strain) but not in mice (NMRI strain). The protein metallothionein (MT) plays an important role in Cd detoxification, and it has been suggested that differential inducibility of pulmonary MT may lead to interspecies susceptibility differences to inhaled Cd. Interstrain differences in the pulmonary response of the MT gene to Cd stimuli have not been examined in rats or mice. We compared pulmonary MT expression in Wistar Furth (WF) rats with that in DBA and C57 mice, following a single 3-h exposure to CdO fumes containing 1 mg Cd/m3. Induction of the MT gene was assessed by the levels of MT-I and MT-II transcripts, MT-protein content, and number of MT-labeled alveolar and bronchiolar epithelial cells immediately after Cd exposure and 1, 3, and 5 days later. Control animals were exposed to air/argon furnace gases. We observed differential intra- and interspecies inducibility of the MT gene in the lung following Cd inhalation. DBA mice exhibited greater levels of MT-mRNA, mainly for the MT-I isoform, MT-protein content, and number of MT positive cells relative to C57 mice. WF rats showed lower transcription and translation responses of the MT gene upon Cd stimuli than C57 mice. The present results, in concert with our previous findings of higher lung cell proliferation in Cd-exposed C57 relative to DBA mice, predict greater susceptibility of C57 to the carcinogenic effects of inhaled Cd. Furthermore, the low transcriptional and translation responses of the MT gene to Cd stimuli in WF rats might explain the higher susceptibility of this rat strain to develop malignant lung tumors after chronic exposure to Cd via inhalation. Parallel to our findings in mice, differences in the responsiveness of lung MT gene may exist across rat strains. Thus intraspecies genetic variability in pulmonary MT may influence the susceptibility of rats or mice to lung carcinogenesis induced by inhalation of Cd compounds.
长期吸入镉（Cd）已被证明可在大鼠（Wistar品系）中诱发肺部肿瘤，但在小鼠（NMRI品系）中则不会。蛋白质金属硫蛋白（MT）在镉解毒过程中发挥着重要作用，有人认为肺部MT的不同诱导性可能导致物种间对吸入镉的易感性差异。大鼠或小鼠中MT基因对镉刺激的肺反应的品系间差异尚未得到研究。我们比较了Wistar Furth（WF）大鼠与DBA和C57小鼠在单次暴露于含1 mg Cd/m³的CdO烟雾3小时后的肺MT表达。在镉暴露后立即以及1、3和5天后，通过MT-I和MT-II转录本水平、MT蛋白含量以及MT标记的肺泡和细支气管上皮细胞数量来评估MT基因的诱导情况。对照动物暴露于空气/氩气炉气体中。我们观察到吸入镉后肺中MT基因在种内和种间的诱导性存在差异。相对于C57小鼠，DBA小鼠表现出更高水平的MT-mRNA，主要是MT-I异构体、MT蛋白含量以及MT阳性细胞数量。WF大鼠在镉刺激下MT基因的转录和翻译反应低于C57小鼠。目前的结果，与我们之前发现的镉暴露的C57小鼠相对于DBA小鼠有更高的肺细胞增殖情况一致，预测C57对吸入镉的致癌作用更易感。此外，WF大鼠中MT基因对镉刺激的低转录和翻译反应可能解释了该大鼠品系在长期吸入镉后发生恶性肺肿瘤的易感性更高。与我们在小鼠中的发现相似，不同大鼠品系的肺MT基因反应性可能存在差异。因此，肺MT的种内遗传变异性可能影响大鼠或小鼠对吸入镉化合物诱导的肺癌发生的易感性。
