Developmental exposure to BDE-99 hinders cerebrovascular growth and disturbs vascular barrier formation in zebrafish larvae.
Developmental exposure to BDE-99 hinders cerebrovascular growth and disturbs vascular barrier formation in zebrafish larvae.
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DOI：
10.1016/j.aquatox.2019.105224
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发表时间：
2019-09
影响因子：
4.5
通讯作者：
X. Zhong;Jianmeng Kang;Jiahuang Qiu;Wenhan Yang;Jingwei Wu;D. Ji;Yuejin E. Yu;Weijian Ke;
中科院分区：
文献类型：
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作者：
X. Zhong;Jianmeng Kang;Jiahuang Qiu;Wenhan Yang;Jingwei Wu;D. Ji;Yuejin E. Yu;Weijian Ke;
多溴联苯醚（PBDEs）分布在整个环境中。尽管暂停使用多溴二苯醚，但由于其持久性，大气和居住环境中的多溴二苯醚浓度仍然很高。环境健康风险仍然令人担忧，其中一个主要的不利影响是神经发育毒性。然而，多溴二苯醚暴露对发育中的大脑的早期反应和影响仍然未知。在本研究中，我们利用斑马鱼模型研究了2,2 ',4,4 '，5-五溴化二苯醚（BDE-99）对早期生命阶段血管生长和血管屏障功能的影响，重点是脑血管。在72 hpf下，0-0.5 μM BDE-99对斑马鱼幼体无普遍毒性作用。BDE-99暴露不会导致躯体血管（包括节间血管（ISV）和总主静脉（CCV））的一般毒性或明显的发育损害。同时，0.05 μM和0.5 μM的BDE-99均可降低脑组织血管密度，下调脑组织vegfa2和vegfr2的表达。此外，在72 hpf时，BDE-99暴露增加了大脑和躯干血管渗漏。头部血管通透性增强。暴露于bde -99的幼虫中，编码紧密连接分子的基因mRNA水平下降，其中头部的inCldn5、zo1和jam3个基因的下降幅度大于躯干。此外，BDE-99暴露后，可诱导tnf -α、il -1β和icam -1等促炎因子，抑制头部神经发育相关基因的表达。综上所述，这些结果表明发育暴露于BDE-99会阻碍脑血管生长并扰乱血管屏障的形成。发育中的斑马鱼的脑血管系统是BDE-99更敏感的靶点，可能是评估多溴二苯醚暴露引起的早期神经发育影响的有前途的工具。
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 ofVEGFAandVEGFR2in 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 inCldn5,Zo1andJamwere detected in the head than in the trunk. Moreover, proinflammatory factors includingTNF-α, IL-1βandICAM-1were 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.