Cortisol-treated zebrafish embryos develop into pro-inflammatory adults with aberrant immune gene regulation [adults]

Chronic early life stress increases adult susceptibility to numerous health problems linked to chronic inflammation. One way that this may occur is via glucocorticoid-induced developmental programming. To gain insight into such programming, we treated zebrafish embryos with cortisol and examined the effects on adults. In adulthood, the treated fish maintained elevated basal cortisol levels in the absence of exogenous cortisol, and constitutively mis-expressed genes involved in defense response and its regulation. Adults derived from cortisol-treated embryos displayed defective tailfin regeneration, heightened basal expression of pro-inflammatory genes, and failure to appropriately regulate those genes following injury or immunological challenge. These results support the hypothesis that chronically elevated glucocorticoid signaling early in life directs development of a pro-inflammatory adult phenotype, at the expense of immunoregulation and somatic regenerative capacity. 30 samples total were analyzed. 9 caudal fins samples (0, 2 and 4dpa), 3 blood samples and 3 muscle samples from adults exposed to DMSO control as embryos. 9 caudal fins samples (0, 2 and 4dpa), 3 blood samples and 3 muscle samples from adults exposed to cortisol (1 micromolar) as embryos.慢性早期生命应激会增加成年个体罹患多种与慢性炎症相关健康问题的易感性。其潜在致病机制之一，是通过糖皮质激素（glucocorticoid）诱导的发育编程实现。为深入解析此类发育编程的调控逻辑，本研究采用皮质醇处理斑马鱼胚胎，并观察其对成年个体的影响。结果显示，在无外源性皮质醇存在的情况下，经皮质醇处理的斑马鱼成年后仍维持基础皮质醇水平升高，且参与防御反应及其调控的基因出现组成型异常表达。源自皮质醇处理胚胎的成年斑马鱼，其尾鳍再生能力存在缺陷，促炎基因的基础表达水平升高，且在损伤或免疫刺激后无法对这些基因进行恰当调控。上述结果支持以下假说：生命早期持续升高的糖皮质激素信号通路活性，会以免疫调控和体细胞再生能力为代价，诱导促炎型成年表型的形成。本研究共计分析30份样本：其中9份尾鳍样本（对应截肢后0、2、4天，即0、2、4dpa）、3份血液样本及3份肌肉样本，其供体成年斑马鱼在胚胎期暴露于二甲基亚砜（DMSO）对照环境；另有9份尾鳍样本（0、2、4dpa）、3份血液样本及3份肌肉样本，其供体成年斑马鱼在胚胎期暴露于1微摩尔浓度的皮质醇环境中。