title: Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness.
abstract: The use of nanoparticles in medicine is ever increasing, and it is important to understand their targeted and non-targeted effects. We have previously shown that nanoparticles can cause DNA damage to cells cultured below a cellular barrier without crossing this barrier. Here, we show that this indirect DNA damage depends on the thickness of the cellular barrier, and it is mediated by signalling through gap junction proteins following the generation of mitochondrial free radicals. Indirect damage was seen across both trophoblast and corneal barriers. Signalling, including cytokine release, occurred only across bilayer and multilayer barriers, but not across monolayer barriers. Indirect toxicity was also observed in mice and using ex vivo explants of the human placenta. If the importance of barrier thickness in signalling is a general feature for all types of barriers, our results may offer a principle with which to limit the adverse effects of nanoparticle exposure and offer new therapeutic approaches.
authors: Bristol Musculoskeletal Research Unit, Clinical Science at North Bristol University of Bristol, Avon Orthopaedic Centre, Southmead Hospital, Bristol.
authors: A
authors: A
authors: Sood
authors: S
authors: S
authors: Salih
authors: D
authors: D
authors: Roh
authors: L
authors: L
authors: Lacharme-Lora
authors: M
authors: M
authors: Parry
authors: B
authors: B
authors: Hardiman
authors: R
authors: R
authors: Keehan
authors: R
authors: R
authors: Grummer
authors: E
authors: E
authors: Winterhager
authors: P J
authors: PJ
authors: Gokhale
authors: P W
authors: PW
authors: Andrews
authors: C
authors: C
authors: Abbott
authors: K
authors: K
authors: Forbes
authors: M
authors: M
authors: Westwood
authors: J D
authors: JD
authors: Aplin
authors: E
authors: E
authors: Ingham
authors: I
authors: I
authors: Papageorgiou
authors: M
authors: M
authors: Berry
authors: J
authors: J
authors: Liu
authors: A D
authors: AD
authors: Dick
authors: R J
authors: RJ
authors: Garland
authors: N
authors: N
authors: Williams
authors: R
authors: R
authors: Singh
authors: A K
authors: AK
authors: Simon
authors: M
authors: M
authors: Lewis
authors: J
authors: J
authors: Ham
authors: L
authors: L
authors: Roger
authors: D M
authors: DM
authors: Baird
authors: L A
authors: LA
authors: Crompton
authors: M A
authors: MA
authors: Caldwell
authors: H
authors: H
authors: Swalwell
authors: M
authors: M
authors: Birch-Machin
authors: G
authors: G
authors: Lopez-Castejon
authors: A
authors: A
authors: Randall
authors: H
authors: H
authors: Lin
authors: M-S
authors: MS
authors: Suleiman
authors: W H
authors: WH
authors: Evans
authors: R
authors: R
authors: Newson
authors: C P
authors: CP
authors: Case
mesh_terms: D000818:Animals; D002858:Chromium Alloys / Q000009:adverse effects* / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004249:DNA Damage; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D053768:Metal Nanoparticles / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009842:Oligopeptides; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D002858:Chromium Alloys; D017630:Connexins; D016207:Cytokines; D005609:Free Radicals; D008051:Lipid Bilayers; D009842:Oligopeptides; C455880:gap 27 peptide