Collins Dalis E, Mulka Kathleen R, Hoenerhoff Mark J, Taichman Russell S, Villano Jason S
Unit for Laboratory Animal Medicine (ULAM), University of Michigan, Ann Arbor, Michigan, Center for Comparative Medicine, Baylor College of Medicine, Houston Texas.
College of Veterinary Medicine, Michigan State University, Lansing, Michigan.
Comp Med. 2017 Feb 1;67(1):11-21.
Estrogen supplementation is a key component of numerous mouse research models but can adversely affect the urinary system. The goal of this study was to develop a clinical scoring system and identify biomarkers of occult urinary tract lesions prior to the development of systemic illness in mice. Ovariectomized or sham-surgery SCID mice were implanted subcutaneously with a placebo pellet or one containing sustained-release estradiol (0.18 mg 60-d release 17β-estradiol). Mice were assessed twice weekly for 4 to 6 wk by using a clinical scoring system that included body condition, general activity, posture, hair coat, hydration, abdominal distension, urine staining of coat and skin, and ability to urinate. Samples were collected weekly for urinalysis, BUN, creatinine, and serum estradiol levels. Terminal samples were analyzed for histopathologic lesions. Compared with placebo controls, estradiolsupplemented mice had higher serum estradiol levels at weeks 2 and 3; significant differences in total clinical scores by the 3-wk time point; and in body condition, general activity, posture, hair coat, and urine staining scores by the 6-wk terminal time point. Urinary tract lesions included hydronephrosis, pyelonephritis, cystitis, and urolithiasis. All mice with urolithiasis had crystalluria, and 5 of the 6 mice with pyelonephritis or hydroureter had dilute urine (that is, specific gravity less than 1.030). However, these findings were not specific to mice with lesions. A total clinical score of 3.5 (maximum, 24) identified estradiol-supplemented mice with 83% specificity and 50% sensitivity, but no single clinical parameter, biomarker, or the total clinical score accurately predicted occult urinary tract lesions. Considering the lesions we observed, prudence is warranted when using pelleted sustained-release estradiol in mice, and important parameters to monitor for animal health include urine staining, body condition score, urine sediment, and urine specific gravity.
雌激素补充是众多小鼠研究模型的关键组成部分，但可能对泌尿系统产生不利影响。本研究的目的是开发一种临床评分系统，并在小鼠全身性疾病发生之前识别隐匿性尿路病变的生物标志物。将去卵巢或假手术的SCID小鼠皮下植入安慰剂药丸或含缓释雌二醇（0.18 mg，60天释放17β - 雌二醇）的药丸。使用包括身体状况、一般活动、姿势、毛发、水合作用、腹胀、被毛和皮肤的尿液染色以及排尿能力的临床评分系统，每周对小鼠进行两次评估，持续4至6周。每周收集样本进行尿液分析、血尿素氮、肌酐和血清雌二醇水平检测。对终末样本进行组织病理学病变分析。与安慰剂对照组相比，补充雌二醇的小鼠在第2周和第3周时血清雌二醇水平较高；在3周时间点时总临床评分有显著差异；在6周终末时间点时身体状况、一般活动、姿势、毛发和尿液染色评分有显著差异。尿路病变包括肾积水、肾盂肾炎、膀胱炎和尿石症。所有患有尿石症的小鼠都有结晶尿，6只患有肾盂肾炎或输尿管积水的小鼠中有5只尿液稀释（即比重小于1.030）。然而，这些发现并非病变小鼠所特有。总临床评分为3.5（满分24分）可识别补充雌二醇的小鼠，特异性为83%，敏感性为50%，但没有单一的临床参数、生物标志物或总临床评分能够准确预测隐匿性尿路病变。考虑到我们观察到的病变，在小鼠中使用丸剂缓释雌二醇时应谨慎，监测动物健康的重要参数包括尿液染色、身体状况评分、尿沉渣和尿比重。
