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Toxicologic Pathology
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Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

Hisham K. Hamadeh

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Brian L. Knight

Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877, USA

Astrid C. Haugen

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Stella Sieber

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Rupesh P. Amin

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Pierre R. Bushel

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Raymond Stoll

Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877, USA

Kerry Blanchard

Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877, USA

Supriya Jayadev

Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877, USA

Raymond W. Tennant

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Michael L. Cunningham

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Cynthia A. Afshari

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Richard S. Paules

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA, paules{at}niehs.nih.gov.

Methapyrilene (MP) exposure of animals can result in an array of adverse pathological responses including hepatotoxicity. This study investigates gene expression and histopathological alterations in response to MP treatment in order to 1) utilize computational approaches to classify samples derived from livers of MP treated rats based on severity of toxicity incurred in the corresponding tissue, 2) to phenotypically anchor gene expression patterns, and 3) to gain insight into mechanism(s) of methapyrilene hepatotoxicity. Large-scale differential gene expression levels associated with the exposure of male Sprague—Dawley rats to the rodent hepatic carcinogen MP for 1, 3, or 7 days after daily dosage with 10 or 100 mg/kg/day were monitored. Hierarchical clustering and principal component analysis were successful in classifying samples in agreement with microscopic observations and revealed low-dose effects that were not observed histopathologically. Data from cDNA microarray analysis corroborated observed histopathological alterations such as hepatocellular necrosis, bile duct hyperplasia, microvesicular vacuolization, and portal inflammation observed in the livers of MP exposed rats and provided insight into the role of specific genes in the studied toxicological processes.

Key Words: Toxicogenomics • gene expression • methapyrilene • toxicity classification • rat liver • histopathology • phenotypic anchorage • hepatotoxicity.

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Toxicologic Pathology, Vol. 30, No. 4, 470-482 (2002)
DOI: 10.1080/01926230290105712
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