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Time- and Dose-based Gene Expression Profiles Produced by a Bile-duct–damaging Chemical, 4,4'-methylene Dianiline, in Mouse Liver in an Acute Phase

¹ School of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 200-701, Republic of Korea
² Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
³ Seoul National University Biomedical Informatics (SNUBI) and Human Genome Research Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
⁴ College of Pharmacy and Bio-MAX Institute, Seoul National University, Seoul 151-742, Republic of Korea
⁵ College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
⁶ Department of Biochemistry, College of Medicine, Ewha Women’s University, Seoul 158-710, Republic of Korea
⁷ College of Medicine, Hanyang University, Seoul 133-891, Republic of Korea
⁸ Toxicogenomics Research Consortium (TGRC), Hanyang University, Seoul 133-891, Republic of Korea

Correspondence: Byung-IL Yoon, DVM, PhD, School of Veterinary Medicine, Kangwon National University, 192-1 Hyoja2-dong, Chuncheon, Kangwon 200-701, Republic of Korea; e-mail:byoon{at}kangwon.ac.kr

A toxicogenomics study was performed in the mouse liver after treatment of a bile-duct–damaging chemical, 4,4'-methylene dianiline (MDA), across multiple doses and sampling times in an acute phase using the AB Expression Array System. Imprinting control region (ICR) mice were given a single oral administration of a low (10 mg/kg b.w.) or high (100 mg/kg b.w.) dose of MDA. Mice were sacrificed six, twenty-four, and seventy-two hours after treatment for serum chemistry, histopathology, and mRNA preparation from liver samples. Treatment with MDA increased liver-toxicity–related enzymes in blood and induced bile-duct cell injury, followed by regeneration. To explore potential biomarker gene profiles, the altered genes were categorized into four expression patterns depending on dose and time. Numerous functionally defined and unclassified genes in each category were up- or down-regulated throughout the period from cellular injury to the recovery phase, verified by RT-PCR. Many genes associated with liver toxicity and diseases belonged to one of these categories. The chemokine-mediated Th1 pathway was implicated in the inflammatory process. The genes associated with oxidative stress, apoptosis, and cell-cycle regulation were also dynamically responsive to MDA treatment. The Wnt/β-catenin signaling pathway was likely responsible for the reconstitution process of the MDA-injured liver.

Key Words: acute liver toxicity • 4,4'-methylene dianiline • mouse • toxicogenomics

Abbreviations: AB, Applied Biosystems • ALT, alanine aminotransferase • AST, aspartate aminotransferase • COA, correspondence analysis • DEA, differential expression analysis • MDA, 4, 4'-methylene dianiline • NO, nitric oxide • ROS, reactive oxygen species

This version was published on July 1, 2008

Toxicologic Pathology, Vol. 36, No. 5, 660-673 (2008)
DOI: 10.1177/0192623308320272


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