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Vascular Effects of GI262570X (PPAR- agonist) in the Brown Adipose Tissue of Han Wistar Rats: A Review of 1-month, 13-week, 27-week and 2-year Oral Toxicity Studies

Department of Pathology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA, cse63957{at}gsk.com

Thomas A. Brodie

Department of Pathology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

H. Roger Brown

Department of Toxicogenomics, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

James B. Nold

Department of Pathology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

Timothy J. Raczniak

Department of Toxicology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

Ronald D. Tyler

Department of Predictive Toxicology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

Ruth M. Lightfoot

Department of Safety Assessment, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

Henry G. Wall

Department of Pathology, GlaxoSmithKline Inc, Research Triangle Park, North Carolina 27709, USA

We describe and discuss microscopic findings in the brown adipose tissue (BAT) blood vessels of Han Wistar rats treated with GI262570X, a peroxisome proliferator-activated receptor- agonist (PPAR- agonist) by oral gavage for 28 days, 13 weeks, 27 weeks, and 2 years. Review of these studies revealed a consistent vascular change, consisting of multifocal fatty infiltration in the BAT of treated rats. A similar vascular change was not seen in other vessels or organs. Microscopically, fatty infiltration was characterized primarily by round, clear vacuoles within the tunica media and/or tunica adventitia of small and medium-sized arteries and arterioles. Occasionally, these vacuoles had peripherally located nuclei and morphologically resembled adipocytes, suggesting a well-characterized PPAR effect (ie, differentiation of stem cells or preadipocytes into mature adipocytes). However, administration of GI262570X up to 2 years failed to induce more severe or progressive lesions in the blood vessels of rat BAT and, in particular, did not result in induction of any atherosclerotic-like lesions or foam cell infiltration. At the longer exposure, there was an apparent reduction of severity and/or incidence, indicating a possible adaptive response. These results suggest that the possibility of generating atherosclerotic-like lesions through prolonged treatment of GI262570X (PPAR- agonist) is highly unlikely in rats.

Key Words: Peroxisome proliferator-activated receptor- agonist • brown adipose tissue • vascular fatty infiltration • adipocyte differentiation • atherosclerosis • Han Wistar rats.

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Toxicologic Pathology, Vol. 30, No. 4, 420-426 (2002)
DOI: 10.1080/01926230290105640


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