Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes

Hawkins, Simon J.; Crompton, Lucy A.; Sood, Aman; Saunders, Margaret; Boyle, Noreen T.; Buckley, Amy; Minogue, Aed�n M.; McComish, Sarah F.; Jim�nez-Moreno, Natalia; Cordero-Llana, Oscar; Stathakos, Petros; Gilmore, Catherine E.; Kelly, Stephen; Lane, Jon D.; Case, C. Patrick; Caldwell, Maeve A.

Abstract

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 ATG4BC74A 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.

• Journal Article Type: Article
• Acceptance Date: Mar 1, 2018
• Online Publication Date: Apr 2, 2018
• Publication Date: 2018-05
• Deposit Date: Apr 21, 2022
• Journal: Nature Nanotechnology
• Print ISSN: 1748-3387
• Electronic ISSN: 1748-3395
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 5
• Pages: 427-433
• DOI: https://doi.org/10.1038/s41565-018-0085-3
• Keywords: Electrical and Electronic Engineering; Condensed Matter Physics; General Materials Science; Biomedical Engineering; Atomic and Molecular Physics, and Optics; Bioengineering
• Public URL: https://uwe-repository.worktribe.com/output/9378332
• Additional Information: Received: 27 March 2015; Accepted: 31 January 2018; First Online: 2 April 2018; : The authors declare no competing interests.