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ToxSci Advance Access originally published online on June 16, 2004
Toxicological Sciences 2004 81(1):243-252; doi:10.1093/toxsci/kfh194
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Toxicological Sciences vol. 81 no. 1 © Society of Toxicology 2004; all rights reserved.

Bis(2-chloroethoxy)methane-Induced Mitochondrial and Myofibrillar Damage: Short-Term Time-Course Study

June Dunnick*,1, JoAnne Johnson{dagger}, John Horton{dagger} and Abraham Nyska{dagger}

* Environmental Toxicology Program, and {dagger} Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Received April 15, 2004; accepted June 6, 2004

Cardiotoxicity induced by 2-, 3-, 5-, and 12-day dermal administration of 400 and 600 mg/kg/day of bis(2-chloroethoxy)methane to F344/N male and female rats was characterized. The severity and incidence of lesions were similar among males and females and in all three regions of the heart examined (atrium, ventricle, interventricular septum). Damage induced by bis(2-chloroethoxy)methane consisted of time-related development of myofiber vacuolation, necrosis, mononuclear-cell infiltration, fibrosis, and atrial thrombosis. Changes were pronounced at day 2, increased in severity at day 3, appeared to decrease at day 5, and resolved by study-day 16 that corresponded to 12 dosings. Ultrastructural analysis of 2- and 5-day 600 mg/kg/day-treated females elucidated the primary site of damage, the mitochondrion, and two types of vacuolation, one that formed as damaged mitochondria became devoid of cristae and their bounding double membranes became reduced to singleness, and the other manifested as distention of the sarcoplasmic reticulum. After the initial damage induced by bis(2-chloroethoxy)methane, or its metabolite, thiodiglycolic acid, protective mechanisms within the heart were apparently initiated, enabling it to cope with the continued exposure to the toxicant while eliminating some damaged myofibers.

Key Words: bis(2-chloroethoxy)methane (CEM); thiodiglycolic acid; cardiotoxicity; vacuolation; mitochondria; sarcoplasmic reticulum (SR); recovery.


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