Thesis

Cobalt toxicity mechanisms in neural cells and brain tissue: understanding the implications for patients with cobalt-chromium alloy orthopaedic implants

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Awarding institution
  • University of Strathclyde
Date of award
  • 2022
Thesis identifier
  • T16458
Person Identifier (Local)
  • 201670674
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Abstract
  • The most recent regulatory update on metal-on-metal (MoM) hip replacements (MDA/2017/018, 2017) has resulted in the monitoring of cobalt and chromium levels in circa 60,000 UK patients for signs of prosthesis failure and local toxicity (Matharu etal., 2018). Multiple medical reports have implicated cobalt in systemic toxicity in prosthetic patients. The consequences of elevated levels of cobalt range from severe cardiac symptoms to diverse neurological complications. In this thesis we have studied the consequences of systemic cobalt toxicity, aka cobaltism, with specific focus on the effect of cobalt in the brain through in vitro and in vivo studies. We compared the effect of cobalt in vitro in neuroblastoma and astrocytoma cells via MTT and Neutral Red (NR) viability test and BrdU proliferation assay. The IC50s obtained indicated that the stalling of DNA synthesis preceded impaired viability. Cobalt effects in both cell lines was dose-dependent as measured by ICP-MS. Neurons appeared to be significantly more sensitive than astrocytes to the same cobalt doses. These investigations revealed cobalt to be toxic at very high concentrations (>100μM) in vitro after 24-72h treatment. For in vivo rat dose and time-response experiments, rodents were injected i.p. with daily cobalt doses. Cobalt significantly accumulated in the hippocampus and pref. cortex of rats after 28 days treatment with 0.5 and 1m/kg B.W. CoCl2. Through RNA-Seq of brain areas we identified a possible metal homeostasis dysregulation. Additionally, the transcripts of several metal-binding protein families such as nuclear receptors, cytochrome P540, carbonic anhydrases and phosphodiesterases were regulated. Mainly, RNA-Seq data showed choroid plexus transcripts, as well as changes in hormone and lipid metabolism. However, target protein levels did not follow gene expression fold change. Our research has found that the choroid plexus is an important target of cobalt toxicity in the rat brain with cobalt levels in blood similar to those of some MoM patients (4-38μg/l). Moreover, we developed new hypotheses about the mechanisms of cobalt toxicity which could be directly investigated in patients and contribute towards finding biomarkers of cobaltism.
Advisor / supervisor
  • Grant, Helen
  • Tate, Rothwelle
Resource Type
DOI

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