Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes
Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes
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DOI：
10.1038/s41565-018-0085-3
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发表时间：
2018-05-01
影响因子：
38.3
通讯作者：
Caldwell, Maeve A.
中科院分区：
文献类型：
--
作者：
Hawkins, Simon J.;Crompton, Lucy A.;Caldwell, Maeve A.
母体纳米颗粒（NP）暴露在胎儿中引起发育毒性而不直接通过NP的可能性先前已被证明，但机制仍然难以捉摸。我们现在证明，暴露的钴和铬纳米颗粒BeWo细胞屏障，在体外模型的人胎盘，触发损伤的自噬通量和释放白细胞介素-6。这有助于改变人类神经祖细胞的分化和衍生的神经元和星形胶质细胞中的DNA损伤。重要的是，神经元DNA损伤是由星形胶质细胞介导的。通过显性阴性人ATG 4 B（C74 A）的过表达抑制BeWo屏障中的自噬降解显著降低星形胶质细胞中的DNA损伤水平。在体内，小鼠的间接NP毒性导致神经发育异常，具有反应性星形胶质细胞增生和胎儿海马中DNA损伤增加。我们的研究结果表明，自噬的潜在重要性，引起NP毒性和风险的间接发育神经毒性后，母体NP暴露。
The potential for maternal nanoparticle (NP) exposures to cause developmental toxicity in the fetus without the direct passage of NPs has previously been shown, but the mechanism remained elusive. We now demonstrate that exposure of cobalt and chromium NPs to BeWo cell barriers, an in vitro model of the human placenta, triggers impairment of the autophagic flux and release of interleukin-6. This contributes to the altered differentiation of human neural progenitor cells and DNA damage in the derived neurons and astrocytes. Crucially, neuronal DNA damage is mediated by astrocytes. Inhibiting the autophagic degradation in the BeWo barrier by overexpression of the dominant-negative human ATG4B(C74A) significantly reduces the levels of DNA damage in astrocytes. In vivo, indirect NP toxicity in mice results in neurodevelopmental abnormalities with reactive astrogliosis and increased DNA damage in the fetal hippocampus. Our results demonstrate the potential importance of autophagy to elicit NP toxicity and the risk of indirect developmental neurotoxicity after maternal NP exposure.