Regenerative Medicine Laboratory, School of Clinical Sciences, University of Bristol, Bristol, UK.
Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
Nat Nanotechnol. 2018 May;13(5):427-433. doi: 10.1038/s41565-018-0085-3. Epub 2018 Apr 2.
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 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.
先前已经表明，母体纳米颗粒 (NP) 暴露即使 NP 没有直接通过，也有可能对胎儿造成发育毒性，但其中的机制仍不清楚。我们现在证明，钴和铬 NP 暴露于 BeWo 细胞屏障（人胎盘的体外模型）会触发自噬通量的损伤和白细胞介素-6 的释放。这导致人神经祖细胞的分化改变和衍生神经元和星形胶质细胞中的 DNA 损伤。至关重要的是，神经元 DNA 损伤是由星形胶质细胞介导的。通过过表达显性失活的人 ATG4B 在 BeWo 屏障中抑制自噬降解，可显著降低星形胶质细胞中的 DNA 损伤水平。在体内，间接 NP 毒性会导致小鼠神经发育异常，海马区出现反应性星形胶质细胞增生和 DNA 损伤增加。我们的研究结果表明，自噬在引发 NP 毒性以及母体 NP 暴露后间接发育神经毒性的风险方面具有重要意义。
