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.

以前已经显示了母体纳米颗粒（NP）暴露而没有直接通过NP引起胎儿发育毒性的潜力，但是该机制仍然难以捉摸。我们现在证明，钴和铬NPs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害和白介素6的释放。这有助于改变人类神经祖细胞的分化以及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。通过过表达显性负性人类ATG4B ^C74A抑制BeWo屏障中的自噬降解大大降低了星形胶质细胞中DNA损伤的水平。在体内，小鼠的间接NP毒性会导致神经发育异常，并伴有反应性星形胶质增生和胎儿海马DNA损伤增加。我们的研究结果表明自噬对引发NP毒性的潜在重要性以及母体NP暴露后间接发展性神经毒性的风险。