Are miRNAs involved in responses to environmental chemicals?

MicroRNA(MiRNA)是一类作为基因表达负调控因子的小RNA。人类和小鼠的基因组分别编码超过1400和700个miRNAs，大多数细胞通路被认为是由miRNAs调控的。然而，关于miRNAs的病理生理作用在很大程度上仍不清楚。因此，我们研究了miRNAs在外源化学物质的毒性反应中的可能参与。在这里，我们搜索了导致2，3，7，8-四氯二苯并对二恶英(TCDD)暴露的小鼠肝脏损伤的miRNAs，发现TCDD以时间依赖的方式差异地下调miR-101a和miR-122。由于miRNA通过抑制其靶基因发挥多种作用，我们对miR-101a的靶基因如环氧合酶-2(COX-2)、Zust同源增强子2(EZH2)和CFos进行了定量，发现这些基因的表达上调，这表明miR-101a下调了这些基因在小鼠肝脏中的表达。COX-2选择性抑制剂NS-398可抑制TCDD诱导的肝损伤。综上所述，本研究证实了TCDD对miR101a和miR122表达的调控作用，并且miR101a的靶基因COX-2在TCDD致小鼠肝损伤中起重要作用。

MicroRNA (miRNA) is a class of small RNA that functions as a negative regulator of gene expression. Human and mouse genomes encode over 1,400 and 700 miRNAs, respectively, and most of the cellular pathways are considered to be modulated by miRNAs. However, it is still largely unknown about the pathophysiological role of miRNAs. Thus, we investigated the possible involvement of miRNAs in the toxic responses to xenobiotic chemicals.Here, we searched for miRNAs responsible for inducing liver damage in mice exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and found that miR-101a and miR-122 are differentially downregulated by TCDD in a time-dependent manner. Since miRNA exerts multiple actions by repressing its target genes, we quantified the target genes of miR-101a, such as cyclooxygenase-2 (COX-2), enhancer of zeste homolog 2 (EZH2), and cFos, and found the upregulation of these genes, which suggests that miR-101a downregulates the expressions of these genes in the mouse liver. A COX-2 selective inhibitor, NS-398, suppressed the onset of TCDD-induced liver damage. In conclusion, this study demonstrated that TCDD dysregulates the expression of miR101a and miR122, and that COX-2, a target gene of miR101a, plays a significant role in liver damage in mice exposed to TCDD.