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Hepatic Gene Expression Changes in Mice Associated with Prolonged Sublethal Microcystin Exposure

¹ Department of Veterinary Pathobiology, Purdue University, West Lafayette, Indiana 47907, USA
² Lilly Research Laboratories, Department of Investigative Toxicology, Eli Lilly and Company, Greenfield, Indiana 46140, USA

Correspondence: Address correspondence to: Dr. Shawn P. Clark, Bristol-Myers Squibb Company, Pharmaceutical Research Institute, 2400 W Lloyd Expressway (P3), Evansville, IN 47721, USA; e-mail:shawn.clark{at}bms.com

Microcystin-LR (MCLR) is an acute hepatotoxicant and suspected carcinogen. Previous chronic studies have individually described hepatic morphologic changes, or alterations in the cytoskeleton, cell signaling or redox pathways. The objective of this study was to characterize chronic effects of MCLR in wild-type mice utilizing gene array analysis, morphology, and plasma chemistries. MCLR was given daily for up to 28 days. RNA from the 28-day study was hybridized onto mouse genechip arrays. RNA from 4 hours, 24 hours, 4 days, 1 day, and 28 days for selected genes was processed for quantitative-PCR. Increases in plasma hepatic enzyme activities and decreases in total protein, albumin and glucose concentrations were identified in MCLR-treated groups at 14 and 28 days. Histologically, marked hepatokaryomegaly was identified in the 14-day MCLR group with the addition of giant cells at 28 days. Major gene transcript changes were identified in the actin organization, cell cycle, apoptotic, cellular redox, cell signaling, albumin metabolism, and glucose homeostasis pathways, and the organic anion transport polypeptide system. Using toxicogenomics, we have identified key molecular pathways involved in chronic sublethal MCLR exposure in wild-type mice, genes participating in those critical pathways and related them to cellular and morphologic alterations seen in this and other studies.

Key Words: Microcystin-LR • Microarray • Liver • Morphology • Redox • Cell cycle • Apoptosis • Actin • Albumin synthesis • OATPS

Abbreviations: MCLR, Microcystin-LR • ALT, alanine aminotransferase • AST, aspartate aminotransferase • ALP, alkaline phosphatase • GGT, gamma glutamyltransferase • OATP, organic anion transporting polypeptide • PP, protein phosphatase

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