The dioxin-like substances polyhalogenated carbazoles (PHCZs) may trigger the aryl hydrocarbon receptor (AhR) signaling pathway. Although the crosstalk between AhR and the hypoxia inducible factor-1 (HIF-1) pathways is generally believed to occur, the exact mechanisms of the HIF-1 pathway in PHCZ toxicity have not been determined. We aimed to elucidate the effect of PHCZs on the HIF-1 pathway and its involvement in the regulation of target genes of HIF-1. Herein, we employed human HepG2 cells transiently transfected with a hypoxia response element (HRE) luciferase reporter to identify PHCZs that could influence HIF-1 pathway. We found that exposure to one of the four selected PHCZs, specifically 1,3,6,8-tetrabromo-9H-carbazole (1368-BCZ), induced a significant enhancement of the activity of HRE activity. In silico data supported 1368-BCZ-induced HIF-1α activity preferentially. Moreover, 1368-BCZ significantly upregulated the expression of HIF-1 target genes, including endothelial growth factor (VEGF) and erythropoietin. Importantly, the stimulated secretion of VEGF by 1368-BCZ promoted the angiogenesis in human umbilical vein endothelial cells. Therefore, the present experimental and computational studies provide new and direct evidence of 1368-BCZ - HIF-1 interaction, which sheds light on the HIF-mediated cardiovascular toxicity and allows a knowledge-based risk assessment of emerging pollutants.

二恶英类物质多卤咔唑（PHCZs）可能触发芳烃受体（AhR）信号通路。尽管通常认为 AhR 和缺氧诱导因子-1 (HIF-1) 通路之间存在串扰，但 HIF-1 通路在 PHCZ 毒性中的确切机制尚未确定。我们旨在阐明 PHCZs 对 HIF-1 通路的影响及其对 HIF-1 靶基因调控的参与。在这里，我们使用用缺氧反应元件 (HRE) 荧光素酶报告基因瞬时转染的人类 HepG2 细胞来鉴定可能影响 HIF-1 通路的 PHCZ。我们发现暴露于四种选定的 PHCZ 中的一种，特别是 1,3,6,8-四溴-9H-咔唑 (1368-BCZ)，会显着增强 HRE 的活性。计算机数据优先支持 1368-BCZ 诱导的 HIF-1α 活性。此外，1368-BCZ 显着上调 HIF-1 靶基因的表达，包括内皮生长因子 (VEGF) 和促红细胞生成素。重要的是，1368-BCZ 刺激的 VEGF 分泌促进了人脐静脉内皮细胞的血管生成。因此，目前的实验和计算研究为 1368-BCZ - HIF-1 相互作用提供了新的直接证据，这揭示了 HIF 介导的心血管毒性，并允许对新兴污染物进行基于知识的风险评估。