Cyanobacterial toxins and liver cancer

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Labine, Meaghan
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Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world today. Over the past decade, the incidence of HCC in Canada has been increasing despite efforts to mitigate disease causing factors such as viral hepatitis B and C infection. Fresh water cyanobacteria are known to release potent hepatotoxins, such as microcystin-LR (MCLR), into drinking and recreational water sources, which have been associated with liver toxicity and HCC. Despite government efforts to limit MCRL contamination, chronic low-dose exposure continues to occur. The purpose of this thesis was to gain an understanding of the potential relationship between chronic low-dose MCLR exposure and HCC. The research contains five areas of investigation; 1) In vitro effects of low-dose MCLR exposure on various hepatocellular cell types, 2) in vitro effects of low-dose MCLR exposure on hepatic stellate cells and fibrosis, 3) in vivo effects of chronic low-dose MCLR exposure on HCC initiation and promotion, 4) in vivo effects of chronic low-dose MCLR exposure on hepatic fibrosis and 5) national and provincial epidemiological analysis investigating the potential association between cyanobacterial hepatotoxins and liver cancer. Our methodology involved; 1) exposing WB-F344, PLC and CFSC-2G hepatic cell lines to varying concentrations of MCLR and observing changes in cell proliferation, protein expression, wound healing and malignant transformation, 2) continuously exposing adult male mice to 1 µg/L of MCLR in their drinking water for seven months, and observing changes in body weight, liver histology, liver enzymes, hepatic fibrosis and HCC development, 3) conducting a national HCC epidemiological study, and determining the relative risk of developing HCC from up-stream factors contributing to cyanobacterial contamination of drinking water sources and 4) conducting a provincial epidemiological study that involved collecting liver cancer incidence data from the Manitoba cancer registry from 1985 to 2007, and temporally and spatially analyzing the association between cancer incidence and MCLR measured in Manitoba lakes. The in vitro results indicate that chronic low-dose exposure to MCLR does not significantly induce cellular characteristics associated with a malignant and/or pro-fibrotic phenotype. In vivo, there were no significant changes in liver pathology, plasma chemistry, histology or tumor development compared to negative controls. Epidemiological analyses conducted at the national and provincial levels revealed similar trends. HCC incidence in Canada was associated with urban residence, immigration and hepatitis B. However, HCC incidence was not found to be influenced by the up-stream cyanobacterial predictive factors; agriculture, cattle and swine density. In Manitoba, the increasing incidence of liver cancer did not temporally or spatially associate with MCLR contamination sites within the province. In conclusion, these results are reassuring in that they suggest that chronic low-dose exposure to MCLR does not initiate or promote the development of HCC at the cellular, systemic or epidemiological levels.
Cyanobacteria, Liver cancer, microcystin, Liver disease, water, cyanotoxin, drinking water, Manitoba