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Title: Indirect genotoxic effects of cobalt chromium nanoparticles across cellular barriers
Author: Salih, Saif
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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There are an estimated 1 million metal-on-metal implants in use worldwide and at least 65,000 of these are in the UK. In 2007 over half of the metal-on-metal hip resurfacings performed in women were in women of childbearing age. These metal implants produce nanoparticle size wear debris. The effects of these nanoparticles are unknown in vivo, but in vitro they can damage a cell's DNA. Nanoparticles are able to induce damage in cells indirectly across a cellular barrier. This effect was shown in vitro across a model barrier of three to five cells' thickness and was dependent upon a signalling mechanism within the barrier and not the direct passage of nanoparticles across the barrier. The placental barrier in vivo is predominantly bi-layered in the first trimester and becomes predominantly monolayered as the pregnancy progresses. To test whether this signalling mechanism could potentially damage a fetus, cobaltchrome nanoparticles were placed above predominantly bi-layered or predominantly mono-layered BeWo barriers and the DNA damage in fibroblasts underneath the barrier was assessed using the alkaline comet assay. To assess whether the DNA damage seen after an indirect nanoparticle exposure could potentially affect a developing foetus, human embryonic stem cells were also indirectly exposed to nanoparticles across predominantly mono-layered and predominantly bi-layered barriers, and their differentiation into the different germ cell layers assessed using A2B5 and CXCR4 as markers for primitive neuroendoderm and mesendoderm respectively. This work confirms nanoparticles induce DNA damage in cells across predominantly bi-layered but not predominalty mono-layered barriers. This DNA damage is dependent upon gap junctions or hemichannels. The generation of free radicals pharmacologically or by hypoxic culture conditions also induces a DNA damaging signal across a predominantly bi-layered but not a predominantly monolayered barrier. Human embryonic stem cell expression of A2B5 was altered following indirect nanoparticle exposure or change of oxygen tension in the predominantly bi-layered barrier but not the predominantly mono-layered barrier. The AS corneal cell also seems to signal in a gap junction or hemichannel dependent manner when it is predominantly bi-layered but not when it is predominantly monolayered. This suggests that this principle may be applicable to other cellular barriers. The human foetus is most susceptible to teratogenic stimuli in the first trimester. Many teratogenic stimuli are thought to involve free radical generation across the placenta in the first trimester. The first trimester is also the time during which the placenta is predominantly bi-layered and so it is speculated that placental barrier signalling in the first trimester may be implicated in teratogenisis. However further epidemiological studies are required to confirm whether orthopaedic implant wear debris is a potential teratogen in a women with metal-on-metal implants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available