Abstract
Cyanobacteria form an essential part of many freshwater ecosystems. However, eutrophication contributes to the growing presence of cyanobacteria worldwide. When the conditions are favourable, these photosynthetic prokaryotes proliferate intensively and can form harmful algal blooms. Not only do such blooms block vital sunlight, cyanobacterial proliferation also leads to deprived oxygen levels. Alarmingly, some cyanobacterlal species produce compounds called cyanotoxins, which form a threat to both aquatic and human life.Microcystin-LR is believed to be one of the most harmful cyanotoxins, exerting its toxicity through the inhibition of several protein phosphatases. Its primary target organ is the liver, though microcystin-LR also exerts toxicity in other organs. Multiple toxicology studies performed in rodents discovered that the toxin causes hepatocellular damage. Furthermore, many -omics publications found multiple biomarkers of microcystin-LR exposure after using proteomic, transcriptomic and metabolomic screening tools.
What most of these studies have in common, however, is that they all applied the toxin In rodents and used dosing strategies that lead to a high bioavailability of the toxin. While this is useful for obtaining more information about microcystin-LR’s mode of action, it is less suitable for human risk assessment, simply because humans are never exposed to such high toxin levels.
The overall aim of this thesis is to get a better understanding of the toxic effects of microcystin-LR in the context of human exposure. The work presented here took a novel approach by using a systems biology approach to study the effect of microcystin-LR, where dosing strategies were chosen that best mimicked real-life human exposure conditions. The translational model used was the pig, an animal that is closer to humans than rodents. This makes the pig more suitable for interpreting the results with a human perspective.
The thesis begins with a literature review on what is currently known about microcystin- LR toxicity, and subsequently provides an overview of all consistent biomarkers of exposure found on the proteome, transcriptome and metabolome levels in at least two publications (Chapter 1). After describing the method development for the -omics tools used in this thesis (Chapter 2) and the rationale for each animal experiment performed (Chapter 3), the effects of low dose microcystin-LR exposure on liver health in pigs are discussed (Chapter 4). Using biomarker screening tools on blood and liver samples, this thesis provides evidence that microcystin-LR may not be as toxic as widely believed, at least in terms of liver disease. Because microcystin-LR has been implicated with colorectal cancer, faeces samples underwent metabolomic analyses (Chapter 5). Preliminary results indicated a toxin effect in the faecal metabolome, suggesting oral exposure to microcystin-LR might affect gut health. Finally, the results of this thesis are reflected upon and future perspectives are provided, as well as some conclusions (Chapter 6).
| Date of Award | Dec 2019 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | EC-Horizon 2020 |
| Supervisor | Christopher Elliott (Supervisor) & Caroline Meharg (Supervisor) |