Yoshida Eiko, Kurita Masaru, Eto Komyo, Kumagai Yoshito, Kaji Toshiyuki
Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
Health and Nursing Facilities for the Aged, Jushindai, Shinwakai, 272 Ikura Kitakata, Tamana 865-0041, Japan.
Toxicology. 2017 Dec 1;392:40-46. doi: 10.1016/j.tox.2017.09.013. Epub 2017 Sep 25.
Methylmercury is an environmental pollutant that exhibits neurotoxicity when ingested, primarily in the form of neuropathological lesions that localize along deep sulci and fissures, in addition to edematous and inflammatory changes in patient cerebrums. These conditions been known to give rise to a variety of ailments that have come to be collectively termed Minamata disease. Since prostaglandins I and E (PGI and PGE) increase vascular permeability and contribute to the progression of inflammatory changes, we hypothesize that methylmercury induces the synthesis of these prostaglandins in brain microvascular endothelial cells and pericytes. To test this theory, human brain microvascular endothelial cells and pericytes were cultured and treated with methylmercury, after which the PGI and PGE released from endothelial cells and/or pericytes were quantified by enzyme-linked immunosorbent assay while protein and mRNA expressions in endothelial cells were analyzed by western blot analysis and real-time reverse transcription polymerase chain reaction, respectively. Experimental results indicate that methylmercury inhibits the activity of protein tyrosine phosphatase 1B, which in turn activates the epidermal growth factor receptor-p38 mitogen-activated protein kinase pathway that induces cyclooxygenase-2 expression. It was also found that the cyclic adenosine 3',5'-monophosphate pathway, which can be activated by PGI and PGE, is involved in methylmercury-induced cyclooxygenase-2 expression. Since it appears that protein tyrosine phosphatase 1 B serves as a sensor protein for methylmercury in these mechanisms, it is our belief that the results of the present study may provide additional insights into the molecular mechanisms responsible for edematous and inflammatory changes in the cerebrum of patients with Minamata disease.
甲基汞是一种环境污染物，摄入后会表现出神经毒性，主要以沿脑沟和脑裂定位的神经病理损伤形式出现，此外患者大脑还会出现水肿和炎症变化。已知这些情况会引发多种疾病，这些疾病统称为水俣病。由于前列腺素I和E（PGI和PGE）会增加血管通透性并促进炎症变化的进展，我们推测甲基汞会诱导脑微血管内皮细胞和周细胞合成这些前列腺素。为了验证这一理论，培养了人脑微血管内皮细胞和周细胞并用甲基汞进行处理，之后通过酶联免疫吸附测定法定量内皮细胞和/或周细胞释放的PGI和PGE，同时分别通过蛋白质印迹分析和实时逆转录聚合酶链反应分析内皮细胞中的蛋白质和mRNA表达。实验结果表明，甲基汞抑制蛋白酪氨酸磷酸酶1B的活性，进而激活表皮生长因子受体-p38丝裂原活化蛋白激酶途径，该途径诱导环氧合酶-2表达。还发现可被PGI和PGE激活的环磷酸腺苷途径参与甲基汞诱导的环氧合酶-2表达。由于在这些机制中蛋白酪氨酸磷酸酶1B似乎充当甲基汞的传感蛋白，我们认为本研究结果可能为水俣病患者大脑水肿和炎症变化的分子机制提供更多见解。
