College of Environment, Research Center of Environmental Science, Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310032, China.
Department of Blood, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Environ Int. 2020 Jul;140:105729. doi: 10.1016/j.envint.2020.105729. Epub 2020 Apr 25.
Polyhalogenated carbazoles (PHCZs) are an emerging class of persistent, bioaccumulative compounds that are structurally and chemically related to dioxins. They have been detected widely in sediment, river, and soil samples, but their environmental risks are largely unknown. Therefore, seven common PHCZs were tested for their endocrine disrupting potential in silico, in vitro, and in vivo. A dual-luciferase reporter gene assay was used to detect receptor-mediated (agonist or antagonistic) activity (concentration range: 10-10 M) against the estrogen receptor α (ERα), glucocorticoid receptor α (GRα), and mineralocorticoid receptor (MR). The alterations in the steroidogenesis pathway were investigated in H295R cells. Antagonistic effects against GRα were observed with five PHCZs, along with an increase in the cortisol levels of H295R cells. The most common effect observed was that of the agonistic activity of ERα, with the molecular docking analysis further indicating that hydrogen bonding and hydrophobic interactions may stabilize the interaction between PHCZs and the estrogen receptor binding pocket. In addition, a seven-day exposure of young female rats to three PHCZs (27-BCZ, 3-BCZ, and 36-BCZ) resulted in changes in serum E2 levels, uterine epithelium cell heights, and relative uterus weights. In conclusion, endocrine-disrupting effects, especially the estrogenic effects, were observed for the tested PHCZs. Such adverse effects of PHCZs on humans and wildlife warrant further thorough investigation.
多卤代咔唑（PHCZs）是一类新兴的持久性、生物累积性化合物，它们在结构和化学上与二恶英有关。它们已在沉积物、河流和土壤样本中广泛检出，但它们的环境风险在很大程度上尚未可知。因此，本文对七种常见的 PHCZ 进行了体内、体外和体内的内分泌干扰潜力测试。双荧光素酶报告基因检测用于检测对雌激素受体α（ERα）、糖皮质激素受体α（GRα）和盐皮质激素受体（MR）的受体介导（激动或拮抗）活性（浓度范围：10-10 M）。在 H295R 细胞中研究了甾体生成途径的改变。五种 PHCZ 对 GRα 表现出拮抗作用，同时 H295R 细胞中的皮质醇水平升高。观察到的最常见的影响是 ERα 的激动活性，分子对接分析进一步表明氢键和疏水相互作用可能稳定 PHCZ 与雌激素受体结合口袋之间的相互作用。此外，对年轻雌性大鼠进行为期七天的暴露，发现三种 PHCZ（27-BCZ、3-BCZ 和 36-BCZ）可改变血清 E2 水平、子宫上皮细胞高度和相对子宫重量。总之，测试的 PHCZ 表现出内分泌干扰作用，特别是雌激素作用。PHCZ 对人类和野生动物的这种不利影响需要进一步深入调查。
