Expression signature of glycidamide, the reactive metabolite of the widespread food carcinogen acrylamide

Recent findings of acrylamide in foods have sparked renewed interest in assessing human health hazards associated with the exposure to this vinyl compound. Acrylamide is tumorigenic at high doses in rodents, but cancer risk projections in the human population remain problematic since the molecular pathogenesis of acrylamide at the low level of dietary uptake is not understood. The present thesis is concerned with the question of whether transcriptional responses may amplify the known genotoxicity of acrylamide. Therefore, we used high-density DNA microarrays and PCR validations to assess genomewide messenger profiles induced in human cells by acrylamide and glycidamide, its more reactive metabolite. The expression changes are characterized by the up-regulation of cytoprotective factors including the glutathione system, carbonyl reductases and various antioxidants. Low-dose experiments indicate that epoxide hydrolase 1 represents the most sensitive biomarker for the internal glycidamide exposure. At higher concentrations, glycidamide induces markers of tumor progression such as steroid hormone activators, regulators of nuclear factor-κB, growth stimulators and apoptosis inhibitors. Concomitantly, growth suppressors and cell adhesion molecules are suppressed. The main implication of these findings for risk assessment is that transcriptional signatures associated with tumor cell progression may be expected only at higher doses that exceed the range of ordinary dietary exposure. Institut für Veterinärpharmakologie und -toxikologie der Vetsuisse-Fakultät Universität Zürich Direktor: Prof. Dr. F. R. Althaus Expression Signature of Glycidamide, the Reactive Metabolite of the Widespread Food Carcinogen Acrylamide Inaugural-Dissertation zur Erlangung der Doktorwürde der Vetsuisse-Fakultät Universität Zürich