多柔比星斑马鱼胚胎心脏发育毒性表现

目的通过观察多柔比星的斑马鱼胚胎心脏毒性表现,为其作为心脏毒性评价模型提供可靠的检测指标。方法选择发育正常的6hpf(hours post fertilization)斑马鱼胚胎暴露于多柔比星2.16～34.48μmol·L-148h。显微镜观察72hpf斑马鱼心血管系统的形态学改变。通过DVC摄像系统测定心率;测量静脉窦-动脉球(SV-BA)间距,HE染色观察斑马鱼心肌结构。结果多柔比星2.16μmol·L-1组斑马鱼心血管系统形态无改变,但心率下降,为(166±5)min-1;SV-BA间距增加,为(237±13)μm。多柔比星4.31μmol·L-1可引起斑马鱼出现心包水肿,心脏畸形,心率减低,为(166±5)min-1;SV-BA间距增加,为(268±13)μm。随着多柔比星浓度增加,斑马鱼出现体长缩短、体节发育异常、脊柱弯曲、卵黄囊水肿、出血、心脏缩小等多种表型改变。心脏组织切片显示,多柔比星8.62μmol·L-1可引起斑马鱼心包腔变大、心脏缩小、心肌层变薄和心肌细胞减少。结论多柔比星对斑马鱼胚胎心脏毒性作用的表现与对哺乳动物的毒性作用表现相同,有望成为评价药物心脏发育毒性的模型。

Cardiotoxicity of doxorubicin on embryonic zebrafish

OBJECTIVE To explore reliable detection parameters for cardiac toxicity evaluation using zebrafish embryos as a model. METHODS Zebrafish embryos at 6 h post fertilization (hpf) were exposed to doxorubicin 2.16-34.48 mol·L^-1 for 48 h. Morphologic changes in the cardiovascular system at 72 hpf were observed under a stereomicroscope. Heart rate was measured by video recordings made with a DVC system. The distance between the sinus venosus and bulbus arteriosus (SV-BA) was examined. Histopathologic sections were observed by HE staining. RESULTS Compared to control group, no morphological changes of the cardiac system of zebrafish embryos in doxorubicin 2.16 μmol·L^-1 group were observed at 72 hpf. However, doxorubicin 2.16 mol·L^-1 produced significant decrease in heart rate (166±5)min^-1 and significant increase in the distance between the sinus venosus and bulbus arteriosus of zebrafish embryos (237±13)μm. In marked contrast to control embryos, zebrafish embryos exposed to doxorubicin 4.31 mol·L^-1 developed pericardial edema, heart malformation, reduced heart rate (165±4)min^-1, and significant increase in the SV-BA distance (268±13)μm. With the concentration of doxorubicin increased, zebrafish embryos exhibited shortened body length, somite dysplasia, spine curvature, yolk sac edema, hemorrhage, and heart narrowing. Doxorubicin 8.62 μmol·L^-1 treated hearts became smaller while heart chambers larger in comparison to controls. Doxorubicin decreased the size of developing hearts by reducing the heart tissue and cardiac myocytes. CONCLUSION Doxorubicin-induced cardiac toxicity has a similar effect on zebrafish embryos to mammalian models, indicating that zebrafish is a promising vertebrate model in vivo for assessment of developmental cardiac toxicity.