Disruption of DNA methylation via S-adenosylhomocysteine is a key process in high incidence liver carcinogenesis in fish

Interactions between epigenome and the environment in biology and in disease are of fundamental importance. The incidence of hepatocellular adenomas in flatfish exceeds 20% in some environments forming a unique opportunity to study environmental tumourigenesis of general relevance to cancer in humans. We report the novel finding of marked DNA methylation and metabolite concentration changes in histopathologically normal tissue distal to tumours in fish liver. A multi-"omics" discovery approach led to targeted and quantitative gene transcription analyses and metabolite analyses of hepatocellular adenomas and histologically normal liver tissue in the same fish. We discovered a remarkable and consistent global DNA hypomethylation, modification of DNA methylation and gene transcription, and disruption of one-carbon metabolism in distal tissue compared to livers of non-tumour-bearing fish. The mechanism of this disruption is linked, not to depletion of S-adenosylmethionine, as is often a feature of mammalian tumours, but to a decrease in choline and elevated S-adenosylhomocysteine, a potent inhibitor of DNA methytransferase. This novel feature of normal-appearing tissue of tumour-bearing fish helps to understand the unprecedentedly high incidence of tumours in fish sampled from the field and adds weight to the controversial epigenetic progenitor model of tumourigenesis. With further studies, the modifications may offer opportunities as biomarkers of exposure to environmental factors influencing disease.