The aryl hydrocarbon receptor (AHR) has endogenous functions in mammalian vascular development and is necessary for mediating the toxic effects of a number of environmental contaminants. Studies in mice have demonstrated that AHR is necessary for the formation of the renal, retinal, and hepatic vasculature. In fish, exposure to the prototypic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces expression of the AHR biomarker cyp1a throughout the developing vasculature and produces vascular malformations in the head and heart. However, it is not known whether the vascular structures that are sensitive to loss of AHR function are also disrupted by aberrant AHR activation. Here, we report that TCDD-exposure in zebrafish disrupts development of 1) the subintestinal venous plexus (SIVP), which vascularizes the developing liver, kidney, gut, and pancreas, and 2) the superficial annular vessel (SAV), an essential component of the retinal vasculature. Furthermore, we determined that TCDD exposure increased the expression of bmp4, a key molecular mediator of SIVP morphogenesis. We hypothesize that the observed SIVP phenotypes contribute to one of the hallmarks of TCDD exposure in fish – the failure of the yolk sac to absorb. Together, our data describe novel TCDD-induced vascular phenotypes and provide molecular insight into critical factors producing the observed vascular malformations.

芳烃受体(AHR)在哺乳动物血管发育中具有内源性功能，是介导许多环境污染物的毒性作用所必需的。对小鼠的研究表明，AHR 是肾、视网膜和肝血管系统形成所必需的。在鱼类中，暴露于原型 AHR 激动剂 2,3,7,8-四氯二苯并二恶英( TCDD) 可诱导 AHR 生物标志物cyp1a的表达贯穿发育中的脉管系统，并在头部和心脏中产生血管畸形。然而，尚不清楚对 AHR 功能丧失敏感的血管结构是否也会被异常 AHR 激活所破坏。在这里，我们报告斑马鱼中的 TCDD 暴露会破坏 1) 肠下静脉丛 (SIVP) 的发育，它为发育中的肝脏、肾脏、肠道和胰腺提供血管，以及 2) 浅环状血管 (SAV)，这是一个重要组成部分的视网膜脉管系统。此外，我们确定 TCDD 暴露增加了bmp4的表达, SIVP 形态发生的关键分子介质。我们假设观察到的 SIVP 表型有助于鱼中 TCDD 暴露的标志之一——卵黄囊无法吸收。总之，我们的数据描述了新的 TCDD 诱导的血管表型，并提供了对产生观察到的血管畸形的关键因素的分子洞察。