氟斑牙大鼠发生纤维瘤:内质网应激和线粒体的激活途径

Fibroma in dental fluorosis rats:the activated pathways of endoplasmic reticulum stress and mitochondria

目的研究氟斑牙大鼠是否可能发生软组织肿瘤,以及瘤组织中内质网应激和线粒体凋亡途径中关键基因的转录水平。方法SD大鼠20只,饮用氟化钠水14个月,观察大鼠精神等状态以及有无包块。用HE染色观察肿瘤组织的病理结构,RT-PCR检测包块组织中内质网应激相关基因IRE1α、PERK、eIF2α、ATF4、GRP78、GRP94、CHOP、XBP1、ATF6和线粒体凋亡途径相关基因JNK、BCL2、Cyt-c、BAX、Casp3的转录水平。结果1例大鼠腹部产生软组织肿瘤,大小3.5 cm×4.0 cm,包膜完整,质地坚硬,活动度高。HE染色结果显示该软组织肿瘤为大量的纤维细胞组成。肿瘤组织与癌旁组织相比,内质网应激信号通路中的GRP78、GRP94、CHOP、IRE1α、PERK、eIF2α、ATF4表达量均上调,而XBP1、ATF6表达量下调;线粒体凋亡途径中BCL2、BAX、Cyt-c、JNK均出现显著上调,Casp3下调。结论氟斑牙SD大鼠能产生纤维瘤,其发病的分子机制与内质网途径和线粒体途径有关,可能为氟化钠致瘤提供了证据,但尚需更多的实验证据。

Objective To investigate whether rats were performed with dental fluorosis develop soft tissue tumors and the transcript levels of key genes in the endoplasmic reticulum stress and mitochondrial apoptosis pathways in tumor tissues.Methods A total of 20 SD rats were treated with sodium fluoride for 14 months.Rats were observed for their mental and other status as well as the presence or absence of tumors.The pathological structures of tumor tissues were tested by HE staining.RT-PCR was performed to detect the endoplasmic reticulum stress-related genes,such as IRE1α,PERK,eIF2α,ATF4,GRP78,GRP94,CHOP,XBP1 and ATF6 in the tumor tissues as well as transcript levels of genes related to the mitochondrial apoptosis pathway,including JNK,BCL2,Cyt-c,BAX,and Casp3.Results A soft tissue tumor was observed in the abdomen of one rat.with a size of(3.5×4.0)cm,which was intact in capsule,hard in texture and high in mobility.HE staining showed that the soft tissue tumors were composed of a large number of fibrous cells.Compared with adjacent tissues,the expressions of GRP78,GRP94,CHOP,IRE1α,PERK,eIF2αand ATF4 were all up-regulated in endoplasmic reticulum stress signaling pathway,while the expressions of XBP1 and ATF6 were down-regulated.In mitochondrial apoptosis pathway,BCL2,BAX,Cyt-c and JNK were up-regulated,while Casp3 was down-regulated.Conclusion SD rats with dental fluorosis can develop fibroma,and its molecular mechanism is related to the endoplasmic reticulum pathway and mitochondrial pathway,which might provide evidence for the tumorigenesis of sodium fluoride.However,more experimental evidence is needed.