Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro
Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro
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DOI：
10.1007/s00204-019-02635-y
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发表时间：
2020-01
影响因子：
6.1
通讯作者：
X. Zhong;Jingwei Wu;Weijian Ke;Yuejin E. Yu;D. Ji;Jianmeng Kang;Jiahuang Qiu;Can Wang;
中科院分区：
文献类型：
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作者：
X. Zhong;Jingwei Wu;Weijian Ke;Yuejin E. Yu;D. Ji;Jianmeng Kang;Jiahuang Qiu;Can Wang;
磷酸三（1，3-二氯-2-丙基）酯（TDCPP）是一种磷基阻燃剂，常见于消费品和婴儿用品。人们对TDCPP暴露和神经发育毒性表示担忧。然而，TDCPP诱导的神经毒性的机制和早期反应知之甚少。本研究探讨了小胶质细胞介导的神经炎症在TDCPP诱导的小鼠和原代细胞神经毒性中的作用。从出生后第10-38天（28天）通过经口灌胃给予C57 BL/6幼仔TDCPP（0、5或50 mg/kg/天）。结果显示，TDCPP暴露28天改变了神经元标记物Tubb 3、Nefh和Nes的基因表达，并导致海马细胞凋亡。在暴露后24 h和28 d，海马中促炎因子IL-1β、TNFα和Ccl 2的mRNA水平呈剂量依赖性增加，伴随着以变形虫样表型为特征的小胶质细胞活化。在使用从新生小鼠分离的原代小胶质细胞的体外研究中，暴露于TDCPP（0-100 μM）24 h导致细胞活化。它还增加了负责炎症反应的基因的表达，包括表面标志物和促炎细胞因子。这些变化以剂量依赖性方式发生。原代小鼠海马神经元的轴突生长受到抑制的处理与条件培养基收获的小胶质细胞暴露于TDCPP。这些结果表明，新生儿暴露于TDCPP通过小胶质细胞介导的炎症诱导神经元损伤。这为TDCPP的神经发育毒性机制提供了新的见解，并表明小胶质细胞是OPFR暴露的敏感反应者。
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10–38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markersTubb3, Nefh,andNes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factorsIl-1β, TnfαandCcl2dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0–100 μM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP’s neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.