Epigenetics in the Regulation of Xenobiotic Responses

Abstract

Xenobiotics are naturally occurring or anthropomorphically derived chemicals which are not generally expected to be present within the body. Through the course of evolution, organisms have developed elaborate ways to cope with xenobiotic exposures. However, the underlying molecular basis by which the protective mechanisms are triggered, and specifically targeted, is not yet fully defined. In particular, the importance of epigenetics (widely considered the mediator of environmental challenges to cells) in the regulation of xenobiotic detoxification responses have received little attention to date. The current work embodies both a „lead-target‟ and genome-wide discovery based assessment of transcriptomic and epigenomic changes induced by mycotoxin challenge in biologically relevant models systems. Managed exposure trials in the ruminant sheep are used to replicate natural exposure in an in vivo context, while human cell line studies allow specifically for empirical testing and validation of functionally relevant pathways inferred from the field testing. Notably, the current work represents the first time that a comprehensive alignment of phenotype, gene expression and multiple forms of epigenetic signature (including miRNA and traditional and novel DNA methylation) has been carried out in a ruminant, a significant technological advance given the relative paucity of genomic information currently available ruminant animal models. The extension of this knowledge into an established human cell culture system, has further underpinned the exploration of additional implied regulatory mechanisms, notably those involving of miRNAs. Seminal observations arising from these studies illustrate: (1) the pivotal involvement of the PI3Kinase and Wnt signalling pathways in the initial response to mycotoxin exposure, (2) the importance of miRNA in further propagation and persistence of this signalling through a hitherto under-appreciated mechanism involving the „suppression of the suppressors‟ of Wnt signalling, (3) the far broader spectrum and complexity of the expected and novel DNA methylation changes (including hydroxymethylation) across target genes influenced by mycotoxin exposure, and (4) the apparent selectivity of terminal gene effector activity in response to specific mycotoxin triggers, notably the CYP2C family of detoxification genes in this instance. Collectively, these data indicate that the degree of „susceptibility‟ to mycotoxin challenge can be defined by the endogenous activity of, and/or inducibility, of terminal detoxification pathways. Further, this susceptibility is embodied in an apparently cryptic epigenetic signature which is only expressed upon challenge, and which determines the stratification of pathological consequence following exposure.