Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-Sen University, No. 74 Zhongshan Rd. 2, Guangzhou, 510080, China.
School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, 510632, China.
Arch Toxicol. 2022 Sep;96(9):2545-2557. doi: 10.1007/s00204-022-03301-6. Epub 2022 Jun 25.
Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)-P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood-brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP's neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.
磷酸三苯酯（TPhP）是一种无卤有机磷阻燃剂，儿童的暴露风险较高。研究发现，TPhP 在发育过程中暴露会导致神经毒性，但具体机制尚不清楚。为了阐明 TPhP 诱导的发育性神经毒性的细胞反应机制，我们在新生后第 10 天（P10）至第 70 天（P70）期间对新生小鼠每日给予 TPhP（0.5、5 或 50mg/kg）。通过单细胞 RNA 测序（scRNA-seq），我们在对照组和低剂量组（代谢产物 DPhP 的内剂量与人类暴露水平相当）的皮质样本中鉴定出 17229 个细胞和 26338 个基因。TPhP 暴露导致神经元、神经干细胞/祖细胞（NSPCs）、内皮细胞和免疫细胞之间的转录异质性改变和细胞间串扰。在 TPhP 暴露的皮质中，我们观察到 NSPC 耗竭、成熟神经元丧失以及由外在和内在免疫细胞介导的伴随神经炎症。此外，我们在焦虑/抑郁样神经行为变化之前观察到血脑屏障破坏。这些结果揭示了 TPhP 神经发育毒性的独特细胞过程，并揭示了神经发生受阻、血管屏障破坏以及伴随的神经炎症是对 TPhP 暴露的敏感反应。我们的研究为 scRNA-seq 在新兴神经毒性污染物的毒性评估中的应用铺平了道路。
