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The purpose of this study was to analyze changes in gene regulation mediated by UCB to determine novel pathways that contribute to UCB\u2010mediated toxicity. We employed microarray analysis to determine changes in gene regulation mediated by UCB at both pro\u2010 (50 \u03bcM) and antioxidant (70 nM) concentrations in Hepa 1c1c7 cells at 1 and 6 h. The changes observed in select genes were validated with qPCR. Using immunoblot analysis, we validated these changes at the protein level for select genes and documented the activation of two proteins involved in the endoplasmic reticulum (ER) stress pathway, eIF2\u03b1 and PERK. Following treatment with 50 \u03bcM UCB, microarray analysis revealed the upregulation of many genes involved in ER stress (<jats:italic>ATF3<\/jats:italic>, <jats:italic>BiP<\/jats:italic>, <jats:italic>CHOP<\/jats:italic>, <jats:italic>Dnajb1<\/jats:italic>, and <jats:italic>Herp<\/jats:italic>). We demonstrate that upregulation of the proapoptotic transcription factor <jats:italic>CHOP<\/jats:italic> results in increased intracellular protein content. It was determined that activation of proteins involved in ER stress was an early event in UCB toxicity as <jats:italic>eIF2<\/jats:italic>\u03b1 and <jats:italic>PERK<\/jats:italic> were both phosphorylated and activated by 1 h posttreatment. We also demonstrate that <jats:italic>procaspase\u201012<\/jats:italic> content, a proposed initiator caspase in ER stress\u2010mediated apoptosis, is decreased by 4 h posttreatment. In conclusion, this study demonstrates that elevated concentrations of UCB (50 \u03bcM) are able to activate select components of the ER stress pathway in Hepa 1c1c7 cells, which may contribute to UCB\u2010mediated apoptosis. \u00a9 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:73\u201388, 2010; Published online in Wiley InterScience (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.interscience.wiley.com\">www.interscience.wiley.com<\/jats:ext-link>). 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