Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
J Immunotoxicol. 2007 Jan;4(1):25-38. doi: 10.1080/15476910601115150.
Toxicological testing of compounds often is conducted at the maximum tolerated dose to identify potential target organs. Toxicities observed at these high doses may result in decreased body weight gain, food consumption and activity. These clinical signs are often associated with a generalized stress response. It has been known that stress may cause increased levels of corticosterone, which causes changes in circulating leukocyte profiles, decreases in thymus and spleen weights and changes in the microscopic structure of lymphoid organs. This makes it difficult to differentiate between stress-related changes and direct toxicity to the immune system in standard non-clinical toxicity testing in rats. In mice, MHC Class II expression was found to be a very sensitive biomarker of stress and maybe useful for the rat. Therefore, the objective of studies presented was to further characterize the effects of corticosterone and stressors on the immune system and identify potential biomarkers of stress in rats. Rats were treated with exogenous corticosterone (20 or 30 mg/kg BID) or ethanol (5 g/kg) for either 1 or 4 days. Restraint stress was also evaluated for a 3-day period. Blood and urine samples were collected during the treatment period for corticosterone measurements. At necropsy, blood samples for leukocyte differentials were collected. Spleen and thymus weights, cellularity, lymphocyte subpopulations and histopathology were also evaluated. Urine corticosterone levels were also investigated as a surrogate to measuring serum corticosterone. The results demonstrate that the pattern of responses to corticosterone or the stressors is different in mice and rats. Although, decreases in MHC Class II were found to be a sensitive indicator of stress in mice, only slight decreases were observed in rats with similar serum corticosterone AUC levels. Decreases in thymus weight were greater than spleen weight with corticosterone or ethanol or restraint stressor. No other single parameter or combination of parameters tested were obvious candidates as sensitive biomarkers of stress in rats. However, the good correlation between urine and serum corticosterone levels suggest that urine corticosterone may be a potential biomarker of stress induced changes to the immune response.
化合物的毒理学测试通常在最大耐受剂量下进行，以确定潜在的靶器官。在这些高剂量下观察到的毒性可能导致体重增加、食物消耗和活动减少。这些临床症状通常与全身应激反应有关。众所周知，应激可能导致皮质酮水平升高，从而导致循环白细胞谱的变化、胸腺和脾脏重量减少以及淋巴器官的微观结构改变。这使得在标准的非临床毒性试验中，很难区分与应激相关的变化和对免疫系统的直接毒性。在小鼠中，MHC 类 II 表达被发现是应激的一个非常敏感的生物标志物，对大鼠可能有用。因此，本研究的目的是进一步描述皮质酮和应激源对免疫系统的影响，并确定大鼠应激的潜在生物标志物。大鼠每天接受外源性皮质酮（20 或 30mg/kg BID）或乙醇（5g/kg）治疗 1 或 4 天。还评估了 3 天的束缚应激。在治疗期间采集血液和尿液样本以测量皮质酮。在尸检时，采集血液样本进行白细胞分类。还评估了脾脏和胸腺重量、细胞数、淋巴细胞亚群和组织病理学。还研究了尿液皮质酮水平作为测量血清皮质酮的替代物。结果表明，对皮质酮或应激源的反应模式在小鼠和大鼠中是不同的。尽管发现 MHC 类 II 的减少是小鼠应激的敏感指标，但在血清皮质酮 AUC 水平相似的大鼠中仅观察到轻微减少。皮质酮或乙醇或束缚应激源导致胸腺重量的减少大于脾脏重量。没有其他单个参数或测试的参数组合是大鼠应激的敏感生物标志物的明显候选者。然而，尿液和血清皮质酮水平之间的良好相关性表明，尿液皮质酮可能是应激引起的免疫反应变化的潜在生物标志物。
