Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier.
Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier.
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DOI：
10.3389/fbioe.2021.622175
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发表时间：
2021
影响因子：
5.7
通讯作者：
Cliffel DE
中科院分区：
文献类型：
--
作者：
Miller DR;McClain ES;Dodds JN;Balinski A;May JC;McLean JA;Cliffel DE
尽管在科学认识和法规方面取得了重大进展，但农药的安全性仍然受到质疑。需要补充分析来识别与化学品暴露相关的失调事件，并利用这些信息来预测生物反应。在这里，我们提出了一个平台，结合模型器官芯片神经血管单元（NVU）与靶向质谱（MS）和电化学分析，以评估有机磷（OP）暴露对血脑屏障（BBB）功能的影响。使用NVU模拟暴露，施用递增剂量的有机磷毒死蜱（CPF）。当浓度高达10 μM时，在整个BBB中均未检测到CPF及其代谢产物（定量限为0.1 μM）。在30 µM CPF及以上时，靶向MS检测到主要尿液代谢物三氯吡啶醇（TCP）穿过BBB（0.025 µM），未检测到其他代谢物。在直接应用CPF的血管腔中，均检测到CPF的两种主要代谢产物TCP和二乙基硫代磷酸盐（DETP）（0.1-5.7 µM）。在第二个实验中，将恒定剂量的10 µM CPF给予NVU，尽管24 h后在BBB中未检测到CPF及其代谢物，但电化学分析检测到BBB两侧的乙酰胆碱水平增加（高达24.8 ± 3.4 µM），并且这些水平在治疗过程中保持较高水平。在直接应用CPF的血管腔中，仅检测到TCP（范围从2 h的0.06 μM到24 h的0.19 μM）。这些结果提供了这种广泛使用的商业杀虫剂引起的实质性破坏的化学证据。这项工作加强了先前观察到的OP代谢和影响机制，验证了NVU用于OP毒理学测试的用途，并为分析这些器官型系统提供了模型平台。
Despite the significant progress in both scientific understanding and regulations, the safety of agricultural pesticides continues to be called into question. The need for complementary analytics to identify dysregulation events associated with chemical exposure and leverage this information to predict biological responses remains. Here, we present a platform that combines a model organ-on-chip neurovascular unit (NVU) with targeted mass spectrometry (MS) and electrochemical analysis to assess the impact of organophosphate (OP) exposure on blood-brain barrier (BBB) function. Using the NVU to simulate exposure, an escalating dose of the organophosphate chlorpyrifos (CPF) was administered. With up to 10 μM, neither CPF nor its metabolites were detected across the BBB (limit of quantitation 0.1 µM). At 30 µM CPF and above, targeted MS detected the main urinary metabolite, trichloropyridinol (TCP), across the BBB (0.025 µM) and no other metabolites. In the vascular chamber where CPF was directly applied, two primary metabolites of CPF, TCP and diethylthiophosphate (DETP), were both detected (0.1–5.7 µM). In a second experiment, a constant dose of 10 µM CPF was administered to the NVU, and though neither CPF nor its metabolites were detected across the BBB after 24 h, electrochemical analysis detected increases in acetylcholine levels on both sides of the BBB (up to 24.8 ± 3.4 µM) and these levels remained high over the course of treatment. In the vascular chamber where CPF was directly applied, only TCP was detected (ranging from 0.06 μM at 2 h to 0.19 μM at 24 h). These results provide chemical evidence of the substantial disruption induced by this widely used commercial pesticide. This work reinforces previously observed OP metabolism and mechanisms of impact, validates the use of the NVU for OP toxicology testing, and provides a model platform for analyzing these organotypic systems.
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