顺铂对小鼠下丘脑-垂体-肾上腺/性腺轴功能的损伤作用及脱氢表雄酮的干预效应  

Injurious Effect of Cisplatin on the Function of Hypothalamus-pituitaryadrenal/gonadal Axis in Mice and the Intervention Effect of Dehydroepiandrosterone

作　　者：潘志强[1] 农淄心 谢海纳 彭佩克 PAN Zhiqiang;NONG Zixin;XIE Haina;PENG Peike(School of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)

机构地区：[1]上海中医药大学中医学院,上海201203

出　　处：《实验动物与比较医学》2023年第3期229-242,共14页Laboratory Animal and Comparative Medicine

基　　金：上海市科学技术委员会科研计划项目“糖皮质激素诱发药源性脾肾虚证小鼠模型的创建及其指标评价体系研究”(19140905000)。

摘　　要：目的研究顺铂(又名顺式-二氯二氨合铂,cis-dichlorodiamineplatinum,DDP)抑制小鼠类固醇激素合成的作用途径,并观察脱氢表雄酮(dehydroepiandrosterone,DHEA)的干预效应。方法将60只成年ICR小鼠随机分为3组:对照组、DDP建模组、DHEA治疗组,每组10只雄性和10只雌性小鼠。DDP建模组小鼠按2.5 mg·kg^(-1)·d^(-1)剂量腹腔注射DDP溶液,每3 d注射1次,共7次;造模同日,对照组小鼠腹腔注射等量的生理盐水;而DEHA治疗组小鼠在予以DDP处理的同时,按8.3 mg·kg^(-1)·d^(-1)剂量给予DHEA灌胃,连续给药21 d。通过旷场、抓力和转棒试验观察小鼠疲劳指标的变化,采用常规组织切片的HE染色法观察肾上腺、睾丸与卵巢组织形态的变化,运用高效液相色谱串联质谱方法检测小鼠血清类固醇激素的含量,运用实时荧光定量PCR和蛋白质印迹技术检测下丘脑、垂体、肾上腺、睾丸和卵巢组织中相关基因的mRNA和蛋白表达水平。结果与对照组比较,DDP建模组雄性与雌性小鼠的体重以及旷场运动能力均显著下降(P<0.05),同时雌性小鼠的抓力和转棒时间也均显著下降(P<0.05);而DHEA治疗组小鼠的上述疲劳指标均显著改善(P<0.05)。DDP建模组雄性小鼠睾丸组织中各级生精细胞排列紊乱且睾丸间质水肿,雌性小鼠卵巢组织中大量原始卵泡被激活,闭锁卵泡增多,卵泡颗粒细胞减少;而DHEA治疗组小鼠睾丸和卵巢受损伤表型均得到显著改善。与对照组比较,DDP建模组雄性与雌性小鼠血清睾酮、二氢睾酮含量均显著降低(P<0.01),雄性小鼠血清孕烯醇酮含量下降而皮质酮含量显著升高(P<0.05),雌性小鼠血清皮质酮含量显著降低(P<0.05);与DDP建模组比较,DHEA治疗组雄性小鼠的孕烯醇酮含量和雌性小鼠的孕酮含量均显著增高(P<0.05),而雌性小鼠的孕烯醇酮含量和雄性小鼠的孕酮含量均显著降低(P<0.05)。与对照组比较,DDP建模组雄性与雌性小鼠的肾�Objective To study the pathway of cis-dichlorodiamineplatinum(DDP)inhibiting the synthesis of steroid hormones in mice,and to observe the intervention effect of dehydroepiandrosterone(DHEA).Methods Sixty adult ICR mice were randomly divided into three groups:control group,DDP modeling group,and DHEA group,with 10 male and 10 female mice in each group.The DDP modeling group mice were intraperitoneally injected with DDP solution at a dose of 2.5 mg·kg^(-1)·d^(-1),once every 3 days,a total of 7 times.On the same day of modeling,the control group mice were injected with an equal amount of physiological saline intraperitoneally.The DEHA treatment group mice were treated with DDP and given a dose of 8.3 mg·kg^(-1)·d^(-1) of DHEA by gavage for 21 consecutive days.The changes of fatigue indexes of mice were observed by open field,grip and rod rotation tests.The morphology changes of adrenal gland,testicular and ovarian tissue were observed by pathological section and HE staining.The levels of serum steroid hormones were detected by high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).The mRNA and protein expression levels of the related genes of the hypothalamus,hypophysis,adrenal,testis and ovary were tested by real-time fluorescent quantitative PCR(RT-qPCR)and Western blotting.Results Compared with control group,both male and female mice in DDP modeling group were significantly losing weight(P<0.05),their abilities in horizontal movement and vertical movement decreased(all P<0.05),and the stay time and grip also significantly decreased(all P<0.05)in female mice.Indexes of fatigue were improved after DHEA supplement(all P<0.05).In the DDP modeling group,the arrangement of spermatogenic cells at all levels in the testicular tissue was disordered and the testicular interstitial edema was observed,and a large number of primordial follicles in the ovarian tissue were activated,the number of atresia follicles increased,and the number of granulosa cells in the follicles decreased;while in the DHEA g

关 键 词：顺铂 脱氢表雄酮 睾丸 卵巢 类固醇激素 小鼠 

分 类 号：R-332[医药卫生] Q95-33[生物学—动物学]