Dalu A, Cronin G M, Lyn-Cook B D, Mehendale H M
Division of Pharmacology and Toxicology, Northeast Louisiana University, Monroe 71209-0470, USA.
J Biochem Toxicol. 1995 Oct;10(5):259-264. doi: 10.1002/jbt.2570100506.
The resiliency of rats during early post-natal development to CCl4 or to an interactive hepatotoxicity of chlordecone (CD) + CCl4 has been shown to be due to an efficient stimulation of tissue repair. The objective of the current study was to investigate if this is due to efficient expression of transforming growth factor-alpha (TGF-alpha) and proto-oncogenes. Postnatally developing (20 day old) and adult (60 day old) male Sprague-Dawley rats were challenged with a single low dose of CCl4 (100 microL/kg, ip) or corn oil. Liver samples were collected during a time course (0-96 h) after the administration of CCl4 and used to examine TGF-alpha and early (c-fos) and late (H-ras and K-ras) proto-oncogenes mRNA expressions. Significant increases in TGF-alpha, H-ras, and K-ras gene expressions were evident as early as 12 hours after CCl4 and peaked between 24 and 48 hours in an age-dependent manner as detected by slot-blot analysis. Results of the study revealed three- and twofold increases in TGF-alpha gene expression in 20 and 60 day old rats, respectively, after CCl4. There were 3.5- and 2.5-fold increases in H-ras and 4.4- and 3.4-fold increases in K-ras in 20 and 60 day old rats, respectively. In contrast, a 10-fold increase in c-fos mRNA expression was evident in 20 day old rats 1 hour after CCl4 treatment, returning to the baseline value by 3 hours, whereas in 60 day old rats, this increase was less than twofold. The overall findings of this study indicate that TGF-alpha and the early and late proto-oncogene mRNA expressions were enhanced in an age- and time-dependent manner in response to a low dose of CCl4. These results further strengthen the view that the remarkable resiliency of rats to hepatotoxicants during early postnatal development is due to substantial increases in stimulation of hepatocellular regeneration and tissue repair mechanisms, leading to regression of liver injury and recovery.
已表明，新生大鼠在出生后早期对四氯化碳（CCl4）或十氯酮（CD）+ CCl4的联合肝毒性具有的恢复力，是由于组织修复得到有效刺激。本研究的目的是调查这是否归因于转化生长因子-α（TGF-α）和原癌基因的有效表达。对出生后发育阶段（20日龄）和成年（60日龄）的雄性Sprague-Dawley大鼠给予单次低剂量的CCl4（100微升/千克，腹腔注射）或玉米油进行挑战。在给予CCl4后的一个时间进程（0 - 96小时）内采集肝脏样本，用于检测TGF-α以及早期（c-fos）和晚期（H-ras和K-ras）原癌基因的mRNA表达。通过狭缝印迹分析检测发现，早在CCl4处理后12小时，TGF-α、H-ras和K-ras基因表达就显著增加，并在24至48小时之间达到峰值，且呈现出年龄依赖性。研究结果显示，CCl4处理后，20日龄和60日龄大鼠的TGF-α基因表达分别增加了3倍和2倍。20日龄和60日龄大鼠的H-ras分别增加了3.5倍和2.5倍，K-ras分别增加了4.4倍和3.4倍。相比之下，CCl4处理1小时后，20日龄大鼠的c-fos mRNA表达增加了10倍，3小时后恢复到基线值；而在60日龄大鼠中，这种增加不到2倍。本研究的总体结果表明，低剂量CCl4刺激下，TGF-α以及早期和晚期原癌基因的mRNA表达以年龄和时间依赖性方式增强。这些结果进一步强化了以下观点：新生大鼠在出生后早期对肝毒性物质具有显著恢复力，是由于肝细胞再生和组织修复机制的刺激大幅增加，从而导致肝损伤消退和恢复。
