Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
Aquat Toxicol. 2019 Sep;214:105224. doi: 10.1016/j.aquatox.2019.105224. Epub 2019 Jun 12.
Polybrominated diphenyl ethers (PBDEs) are distributed throughout the environment. Despite a moratorium on their use, concentrations of PBDEs in the atmosphere and in residential environments remain high due to their persistence. The environmental health risks remain concerning and one of the major adverse effects is neurodevelopmental toxicity. However, the early response and effects of PBDEs exposure on the developing brain remain unknown. In the present study, we investigated the impacts of 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) on vascular growth and vascular barrier function with an emphasis on cerebral blood vessels, in the early life stages, using a zebrafish model. No general toxicity was observed in exposing zebrafish larvae to 0-0.5 μM BDE-99 at 72 hpf. BDE-99 exposure resulted in neither general toxicity nor pronounced developmental impairment in somatic blood vessels, including intersegmental vessels (ISV) and common cardinal veins (CCV). Meanwhile, both 0.05 μM and 0.5 μM of BDE-99 reduced cerebrovascular density as well as down-regulation of VEGFA and VEGFR2 in the head. In addition, BDE-99 exposure increased vascular leakage, both in cerebral and truncal vasculature at 72 hpf. The accentuated vascular permeability was observed in the head. The mRNA levels of genes encoding tight junction molecules decreased in the BDE-99-exposed larvae, and more robust reductions in Cldn5, Zo1 and Jam were detected in the head than in the trunk. Moreover, proinflammatory factors including TNF-α, IL-1β and ICAM-1 were induced, and the expression of neurodevelopment-related genes was suppressed in the head following BDE-99 exposure. Taken together, these results reveal that developmental exposure to BDE-99 impedes cerebrovascular growth and disturbs vascular barrier formation. The cerebral vasculature in developing zebrafish, a more sensitive target for BDE-99, may be a promising tool for the assessment of the early neurodevelopmental effects due to PBDEs exposure.
多溴二苯醚（PBDEs）广泛分布于环境中。尽管已经禁止使用，但由于其持久性，大气和居住环境中的 PBDEs 浓度仍然很高。环境健康风险仍然令人担忧，其中一个主要的不良影响是神经发育毒性。然而，PBDE 暴露对发育中大脑的早期反应和影响仍不清楚。在本研究中，我们使用斑马鱼模型研究了 2,2',4,4',5-五溴二苯醚（BDE-99）在生命早期阶段对血管生长和血管屏障功能的影响，重点研究了脑血管。在 72 hpf 时，暴露于 0-0.5μM BDE-99 的斑马鱼幼虫未观察到一般毒性。BDE-99 暴露既没有导致一般毒性，也没有明显损害体血管的发育，包括节间血管（ISV）和普通头静脉（CCV）。同时，0.05μM 和 0.5μM 的 BDE-99 均降低了脑血管密度，并下调了头部的 VEGFA 和 VEGFR2。此外，BDE-99 暴露在 72 hpf 时增加了脑和躯干血管的血管渗漏。头部观察到血管通透性增加。BDE-99 暴露的幼虫中编码紧密连接分子的基因的 mRNA 水平降低，并且在头部比在躯干中更明显地检测到 Cldn5、Zo1 和 Jam 的减少。此外，BDE-99 暴露后诱导了促炎因子，如 TNF-α、IL-1β 和 ICAM-1，并抑制了头部的神经发育相关基因的表达。综上所述，这些结果表明，发育过程中暴露于 BDE-99 会阻碍脑血管生长并扰乱血管屏障形成。发育中的斑马鱼的脑血管对 BDE-99 更敏感，可能是评估 PBDE 暴露引起的早期神经发育影响的有前途的工具。
