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Occult Cardiotoxicity: Subtoxic Dosage of Bis(2-chloroethoxy)methane Impairs Cardiac Response to Simulated Ischemic Injury

¹ Department of Pathology, Shaare Zedek Medical Center, Jerusalem, 91031, Israel
² The Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah—Hebrew University Medical Center, Jerusalem, 91120, Israel
³ National Institutes of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
⁴ Toxicologic Pathology, Timrat, and Sackler Medical School, Tel-Aviv University, 23840, Israel

Correspondence: Address correspondence to: Herzl Schwalb, The Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah–Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel; e-mail:schwalb{at}hadassah.org.il

The effect of Bis(2-chloroethoxy)methane (CEM) on myocardial response to ischemia was tested in rats. CEM was dermally applied for 3 days to F344/N male rats, at 0, 100, 400, or 600 mg/kg/d. Subsequently, left ventricular sections were prepared from each rat heart. Part of the sections from each heart were exposed to 90 minutes of simulated ischemia, followed by 90 minutes of reoxygenation. The rest of the sections were continuously oxygenated. Mitochondrial activity was assessed in the sections by the MTT colorimetric assay, reflecting dehydrogenases redox activity. Myocardial toxicity occurred in response to 400 and 600 mg/kg, characterized by myofiber vacuoles, necrosis, and mononuclear infiltrates. The latter dose was lethal. In sections from rats treated with 400 mg/kg CEM, redox activity was decreased by 21% (p < 0.01) in oxygenated conditions and by 45% (p < 0.01) in ischemia-reoxygenation, compared to controls. Hearts of rats treated with 100 mg/kg/d CEM showed normal histology. Their mitochondrial activity did not differ from that of untreated rat hearts in oxygenated conditions. However, in ischemia-reoxygenation, their redox activity was significantly lower (by 46%, p < 0.01) than that of untreated rat hearts. These results demonstrate that subtoxic dosage of a cardiotoxic agent may cause occult cardiotoxicity, reflected by impaired response to ischemia.

Key Words: Bis(2-chloroethoxy)methane (CEM) • cardiotoxicity; 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) • Energy metabolism

Abbreviations: CEM, Bis(2-chloroethoxy)methane • LV, Left ventricle, left ventricular • MTT, 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide • PBS, phosphate-buffered saline • G-PBS, phosphate-buffered saline containing glucose • O₂-G-PBS, phosphate-buffered saline containing glucose, aerated with O₂ • N₂-PBS, phosphate-buffered saline without glucose, aerated with N₂

Toxicologic Pathology, Vol. 35, No. 3, 383-387 (2007)
DOI: 10.1080/01926230701230338


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