School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China.
Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, Shandong, China.
Environ Toxicol. 2021 Jul;36(7):1412-1421. doi: 10.1002/tox.23137. Epub 2021 Mar 21.
Environmental exposure to lead (Pb) can damage to the central nervous system (CNS) in humans. High-fat diet (HFD) also has been suggested to impair neurocognitive function. Blood-brain barrier (BBB) is a rigorous permeability barrier for maintaining homeostasis of CNS. The damage of BBB caused by tight junctions (TJs) disruption is central to the etiology of various CNS disorders. This study aimed to investigate whether HFD could exacerbate Pb exposure induced the destruction of BBB integrity by TJs disruption. To this end, we measured cell viability assay, trans-endothelial electrical resistance assay, horseradish peroxidase flux measurement, Western blot analysis, and immunofluorescence experiments. The results showed that palmitic acid (PA), the most common saturated fatty acid found in the human body, can increase the permeability of the BBB in vitro which formed in bEnd.3 cells induced by Pb exposure, and decrease the expression of TJs, such as zonula occludins-1 (ZO-1) and occludin. Besides, we found that PA could promote the up-regulation of matrix metalloproteinase (MMP)-9 expression and activate the c-Jun N-terminal kinase (JNK) pathway induced by Pb. MMP-9 inhibitor or JNK inhibitor could increase BBB integrity and up-regulate the expressions of ZO-1 and occludin after treatment, respectively. Moreover, the JNK inhibitor could down-regulate the expression of MMP-9. In conclusion, these results suggested that HFD exacerbates Pb-induced BBB disruption by disrupting TJs integrity. This may be because PA promotes the activation of JNK pathway and then up-regulated the expression of MMP-9 after Pb-exposure. It is suggested that people with HFD exposed to environmental Pb may cause more serious damage to the CNS.
环境铅（Pb）暴露会损害人类中枢神经系统（CNS）。高脂肪饮食（HFD）也被认为会损害神经认知功能。血脑屏障（BBB）是维持中枢神经系统内环境稳定的严格通透性屏障。紧密连接（TJ）破坏引起的 BBB 损伤是各种中枢神经系统疾病发病机制的核心。本研究旨在探讨 HFD 是否会加剧 Pb 暴露通过 TJ 破坏引起的 BBB 完整性破坏。为此，我们进行了细胞活力测定、跨内皮电阻测定、辣根过氧化物酶通量测定、Western blot 分析和免疫荧光实验。结果表明，在体外，人体中最常见的饱和脂肪酸棕榈酸（PA）可增加由 Pb 暴露诱导的 bEnd.3 细胞形成的 BBB 的通透性，并降低 TJ 的表达，如闭合蛋白-1（ZO-1）和封闭蛋白。此外，我们发现 PA 可促进 Pb 诱导的基质金属蛋白酶（MMP）-9 表达上调和 c-Jun N-末端激酶（JNK）通路激活。MMP-9 抑制剂或 JNK 抑制剂分别处理后可增加 BBB 完整性并上调 ZO-1 和封闭蛋白的表达。此外，JNK 抑制剂可下调 MMP-9 的表达。总之，这些结果表明 HFD 通过破坏 TJ 完整性加剧了 Pb 诱导的 BBB 破坏。这可能是因为 PA 促进了 JNK 通路的激活，然后在 Pb 暴露后上调了 MMP-9 的表达。这表明 HFD 暴露于环境 Pb 的人可能会对中枢神经系统造成更严重的损害。
