3,6-Dibromocarbazole is a novel environmental contaminant which is currently detected in several environmental media worldwide. This work aims to investigate the anti-glucocorticoid potency and endocrine disrupting effects of 3,6-dibromocarbazole. In vitro experiments indicated that 3,6-dibromocarbazole possessed glucocorticoid receptor (GR) antagonistic activity and inhibited dexamethasone-induced GR nuclear translocation. 3,6-Dibromocarbazole reduced the expression levels of glucocorticoid responsive genes including glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), fatty acid synthase (FAS), and tyrosine aminotransferase (TAT), and further disrupted the protein expression of two key enzymes PEPCK and FAS in gluconeogenesis. In vivo experiments showed that 3,6-dibromocarbazole induced abnormal development of zebrafish embryos and disrupted the major neurohormones involved in activation of hypothalamic-pituitary-adrenocortical (HPA) axis in zebrafish larvae. The results of molecular docking and molecular dynamics simulation contributed to explain the antagonistic effect of 3,6-dibromocarbazole. Taken together, this work identified 3,6-dibromocarbazole as a GR antagonist, which might exert endocrine disrupting effects by interfering the pathway of gluconeogenesis.

3,6-二溴咔唑是一种新型环境污染物，目前在全球多种环境介质中均检测到。本工作旨在研究 3,6-二溴咔唑的抗糖皮质激素效力和内分泌干扰作用。体外实验表明，3,6-二溴咔唑具有糖皮质激素受体（GR）拮抗活性，并能抑制地塞米松诱导的GR核转位。3,6-二溴咔唑降低糖皮质激素反应基因的表达水平，包括葡萄糖-6-磷酸酶（G6Pase）、磷酸烯醇丙酮酸羧激酶（PEPCK）、脂肪酸合酶（FAS）和酪氨酸转氨酶（TAT），并进一步破坏糖皮质激素反应基因的蛋白质表达糖异生过程中的两种关键酶PEPCK和FAS。体内实验表明，3,6-二溴咔唑可诱导斑马鱼胚胎发育异常，并扰乱斑马鱼幼虫下丘脑-垂体-肾上腺皮质 (HPA) 轴激活中涉及的主要神经激素。分子对接和分子动力学模拟的结果有助于解释3,6-二溴咔唑的拮抗作用。综上所述，这项工作将 3,6-二溴咔唑确定为 GR 拮抗剂，它可能通过干扰糖异生途径发挥内分泌干扰作用。