Study on the Mechanism Involved in Nanoparticles-Induced Tight Junction and Aquaporins Damages in Endothelial Cells, as Well as the Effects on Physiological Function of Endothelial Barriers

Nanoparticles (NPs) usually exhibit novel physiochemical properties (such as small-scale effect) that are different from bulk materials. After exposure, NPs are absorbed and bio-distributed throughout whole body via systemic circulation. Also, NPs may easily penetrate cell barriers. The blood-brain barrier (BBB) and placental barrier (PB) are mainly comprised of endothelial cells, which line the interior surface of blood vessels (as a physical barrier). BBB is impermeable to most xenobiotic. The selective permeability of BBB protects CNS from xenobiotic damages; as well as the PB, which separates maternal and fetal blood, and protects embryogenesis from maternal xenobiotic. Aside of endothelial cells, the neurovascular units of the BBB also arises from neural cells (astrocytes and pericytes); the PB is composed together with endothelial cells, cytotrophoblasts and syncytiotrophoblasts. Structurally, endothelial barrier is formed by numerous transmembrane proteins (e.g., occludin, claudins, and junctional adhesion molecules), which seal the paracellular cleft by locally dimerizing with each other, that so-called the tight junction (TJ). Water is transferred across the endothelial barrier through both the paracellular and transcellular pathways, and its transfer may be facilitated by aquaporins. Damages in TJ structure and aquaporins will cause the leakiness of BBB/and PB, result in the pathogenesis of various CNS diseases and reproductive toxicity. In this 3-year proposal, we will focus on the molecular mechanisms (such as NP-specific signaling and autophagy pathway) involved in NP-mediated TJ protein/and aquaporins degradation. The changes in paracellular permeability will be evaluated in vitro and in vivo. Moreover, the pathogenesis resulted from BBB/or PB damages will also be studied, either in gold-NP- or in titanium dioxide-NP-treated models (if necessary, studies will also be conducted to barrier-composed, non-endothelial cells). The study aims are summarized by years. 1st year: Gold-NPs increase BBB permeability by altering components of endothelial TJs. 2nd year: Dose NP-induced autophagy play a crucial role in downregulation rd of endothelial TJ proteins and aquaporins? 3 year: Dose NP-mediated TJ protein/and AQPs degradation increase PB permeability, change PB development, and cause reproductive toxicity? Finally, the outcomes of this proposal will be valuable in legislation, risk management and risk communication.