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

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

doi:10.1038/s41565-018-0085-3

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

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

^*Corresponding author for this work

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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 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.

Original language	English
Pages (from-to)	427-433
Number of pages	7
Journal	Nature Nanotechnology
Volume	13
Early online date	2 Apr 2018
DOIs	https://doi.org/10.1038/s41565-018-0085-3
Publication status	Published - 2 Apr 2018

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Significant contribution by JDL and members of the Lane lab (LC; PS; NJ-M).

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Hawkins, S. J., Crompton, L. A., Sood, A., Saunders, M., Boyle, N. T., Buckley, A., Minogue, A. M., McComish, S. F., Jiménez-Moreno, N., Cordero-Llana, O., Stathakos, P., Gilmore, C. E., Kelly, S., Lane, J. D., Case, C. P., & Caldwell, M. A. (2018). Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes. Nature Nanotechnology, 13, 427-433. https://doi.org/10.1038/s41565-018-0085-3

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

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.",

author = "Hawkins, {Simon J.} and Crompton, {Lucy A.} and Aman Sood and Margaret Saunders and Boyle, {Noreen T.} and Amy Buckley and Minogue, {Aed{\'i}n M.} and McComish, {Sarah F.} and Natalia Jim{\'e}nez-Moreno and Oscar Cordero-Llana and Petros Stathakos and Gilmore, {Catherine E.} and Stephen Kelly and Lane, {Jon D.} and Case, {C. Patrick} and Caldwell, {Maeve A.}",

note = "Significant contribution by JDL and members of the Lane lab (LC; PS; NJ-M).",

year = "2018",

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doi = "10.1038/s41565-018-0085-3",

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Hawkins, SJ, Crompton, LA, Sood, A, Saunders, M, Boyle, NT, Buckley, A, Minogue, AM, McComish, SF, Jiménez-Moreno, N, Cordero-Llana, O, Stathakos, P, Gilmore, CE, Kelly, S, Lane, JD , Case, CP & Caldwell, MA 2018, 'Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes', Nature Nanotechnology, vol. 13, pp. 427-433. https://doi.org/10.1038/s41565-018-0085-3

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T1 - Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes

AU - Hawkins, Simon J.

AU - Crompton, Lucy A.

AU - Sood, Aman

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AU - Boyle, Noreen T.

AU - Buckley, Amy

AU - Minogue, Aedín M.

AU - McComish, Sarah F.

AU - Jiménez-Moreno, Natalia

AU - Cordero-Llana, Oscar

AU - Stathakos, Petros

AU - Gilmore, Catherine E.

AU - Kelly, Stephen

AU - Lane, Jon D.

AU - Case, C. Patrick

AU - Caldwell, Maeve A.

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N2 - 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.

AB - 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.

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SP - 427

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JO - Nature Nanotechnology

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

Abstract

Bibliographical note

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Reciprocal Autophagy Control by the LIM Homeodomain Transcription Factors LMX1A and LMX1B Safeguards Human Midbrain Dopaminergic Neurons

Wolfson Bioimaging Facility

Professor Jon D Lane

Cite this

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

Abstract

Bibliographical note

Access to Document

Handle.net

Other files and links

Fingerprint

Student theses

Reciprocal Autophagy Control by the LIM Homeodomain Transcription Factors LMX1A and LMX1B Safeguards Human Midbrain Dopaminergic Neurons

Equipment

Wolfson Bioimaging Facility

Profiles

Professor Jon D Lane

Cite this