Three-dimensional (3D) brain microphysiological system for organophosphates and neurochemical agent toxicity screening
Three-dimensional (3D) brain microphysiological system for organophosphates and neurochemical agent toxicity screening
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DOI：
10.1371/journal.pone.0224657
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发表时间：
2019-11-08
期刊：
影响因子：
3.7
通讯作者：
Yun, Yeoheung
中科院分区：
文献类型：
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作者：
Liu, Lumei;Koo, Youngmi;Yun, Yeoheung
我们研究了3D四培养脑微生理系统(BMPS)在神经毒性化学制剂筛选中的潜在应用。该平台由含有细胞外基质(ECM)包埋的神经母细胞瘤细胞、小胶质细胞和星形胶质细胞的神经元组织和具有动态血流和无膜内皮层培养的血管组织组成。我们测试了这个模型的更广泛的适用性，重点是有机磷(OPS)、马拉硫磷(MT)、对硫磷(PT)和毒死蜱(CPF)，以及与GABA和/或阿片受体系统相互作用的化学物质，包括蝇毒酚(MUS)、右美沙芬(DXM)和乙醇(EtoH)。我们通过测量BMPS平台对屏障完整性、乙酰胆碱酯酶(AChE)抑制、活性和残留OP浓度的神经毒性影响来验证BMPS平台。结果表明，有机磷农药可穿透模型血脑屏障，抑制AChE活性。DXM、MUS和Etoh也可穿透血脑屏障，并引起中度毒性。结果与可获得的活体数据有很好的相关性。此外，我们建立的基于电子生理学的药代动力学/药效学(PBPK/PD)模型的模拟结果与体内和体外数据显示出很好的一致性。总之，这篇论文展示了一种无膜四种培养的BMPS的潜在用途，它可以概括大脑的复杂性，作为一种经济有效的动物模型替代方案。
We investigated a potential use of a 3D tetraculture brain microphysiological system (BMPS) for neurotoxic chemical agent screening. This platform consists of neuronal tissue with extracellular matrix (ECM)-embedded neuroblastoma cells, microglia, and astrocytes, and vascular tissue with dynamic flow and membrane-free culture of the endothelial layer. We tested the broader applicability of this model, focusing on organophosphates (OPs) Malathion (MT), Parathion (PT), and Chlorpyrifos (CPF), and chemicals that interact with GABA and/or opioid receptor systems, including Muscimol (MUS), Dextromethorphan (DXM), and Ethanol (EtOH). We validated the BMPS platform by measuring the neurotoxic effects on barrier integrity, acetylcholinesterase (AChE) inhibition, viability, and residual OP concentration. The results show that OPs penetrated the model blood brain barrier (BBB) and inhibited AChE activity. DXM, MUS, and EtOH also penetrated the BBB and induced moderate toxicity. The results correlate well with available in vivo data. In addition, simulation results from an in silico physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model that we generated show good agreement with in vivo and in vitro data. In conclusion, this paper demonstrates the potential utility of a membrane-free tetraculture BMPS that can recapitulate brain complexity as a cost-effective alternative to animal models.