Penatzer Julia A, Miller Julie V, Prince Nicole, Shaw Misa, Lynch Cayla, Newman Mackenzie, Hobbs Gerald R, Boyd Jonathan W
C. Eugene Bennett Department of Chemistry, West Virginia University, Morvantown, WV, USA.
Cardno ChemRisk, Pittsburgh, PA, USA.
Heliyon. 2021 Jul 12;7(7):e07552. doi: 10.1016/j.heliyon.2021.e07552. eCollection 2021 Jul.
Veterans from the 1990-91 Gulf War were exposed to acetylcholinesterase inhibitors (AChEIs), and, following service, an estimated one-third began suffering from a medically unexplained, multi-symptom illness termed Gulf War Illness (GWI). Previous research has developed validated rodent models that include exposure to exogenous corticosterone (CORT) and AChEIs to simulate high stress and chemical exposures encountered in theater. This combination of exposures in mice resulted in a marked increase in neuroinflammation, which is a common symptom of veterans suffering from GWI. To further elucidate the mechanisms associated with these mouse models of GWI, an investigation into intracellular responses in the cortex were performed to characterize the early cellular signaling changes associated with this exposure-initiated neuroinflammation.
Adult male C57BL/6J mice were exposed to CORT in the drinking water (200 μg/mL) for 7 days followed by a single intraperitoneal injection of diisopropyl fluorophosphate (DFP; 4.0 mg/kg) or chlorpyrifos oxon (CPO; 8.0 mg/kg), on day 8 and euthanized 0.5, 2, and 24 h post-injection. Eleven post-translationally modified protein targets were measured using a multiplexed ELISA.
Phosphoprotein responses were found to be exposure specific following AChEI insult, with and without CORT. Specifically, CORT + CPO exposure was found to sequentially activate several phosphoproteins involved in mitogen activated protein kinase signaling (p-MEK1/2, p-ERK1/2, and p-JNK). DFP alone similarly increased proteins in this pathway (p-RPS6, and p-JNK), but the addition of CORT ameliorated these affects.
The results of this study provide insight into differentially activated pathways depending on AChEI in these GWI models.
1990 - 1991年海湾战争的退伍军人接触过乙酰胆碱酯酶抑制剂（AChEIs），服役后，估计有三分之一的人开始患上一种病因不明的多症状疾病，称为海湾战争病（GWI）。先前的研究已经开发出经过验证的啮齿动物模型，包括暴露于外源性皮质酮（CORT）和AChEIs，以模拟在战区遇到的高压力和化学暴露。小鼠的这种暴露组合导致神经炎症显著增加，这是患有GWI的退伍军人的常见症状。为了进一步阐明与这些GWI小鼠模型相关的机制，对皮质中的细胞内反应进行了研究，以表征与这种暴露引发的神经炎症相关的早期细胞信号变化。
成年雄性C57BL/6J小鼠在饮用水中暴露于CORT（200μg/mL）7天，然后在第8天单次腹腔注射二异丙基氟磷酸酯（DFP；4.0mg/kg）或毒死蜱氧磷（CPO；8.0mg/kg），并在注射后0.5、2和24小时实施安乐死。使用多重ELISA测量11个翻译后修饰的蛋白质靶点。
发现磷蛋白反应在有或没有CORT的情况下，在AChEI损伤后具有暴露特异性。具体而言，发现CORT + CPO暴露会依次激活几种参与丝裂原活化蛋白激酶信号传导的磷蛋白（p-MEK1/2、p-ERK1/2和p-JNK）。单独的DFP同样增加了该途径中的蛋白质（p-RPS6和p-JNK），但添加CORT可改善这些影响。
本研究结果为这些GWI模型中依赖AChEI的差异激活途径提供了见解。
