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ToxSci Advance Access published online on February 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi123
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Toxicological Sciences © The Author [2005]. Published by Oxford University Press [on behalf of the Society of Toxicology]. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 11, 2005
Accepted February 15, 2005

Reproductive and Developmental Toxicology

DIVERGENT ROLES FOR GLUTATHIONE IN LINDANE-INDUCED ACUTE AND DELAYED-ONSET INHIBITION OF RAT MYOMETRIAL GAP JUNCTIONS

Rita Loch Caruso 1*, Brad L. Upham 2, Craig Harris 3, and James E. Trosko 4

1 Toxicology Program, Department of Environmental Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029
2 National Food Safety & Toxicology Center, Department of Pediatrics and Human Development, Michigan State University, 243 Food Safety, East Lansing , MI 48824-1302
3 Toxicology Program, Department of Environmental Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029
4 National Food Safety & Toxicology Center, Department of Pediatrics and Human Development, Michigan State University, 246 Food Safety, East Lansing , MI 48824-1302

* To whom correspondence should be addressed.
Rita Loch Caruso, E-mail: rlc{at}umich.edu


  Abstract

Previous studies showed that the insecticide lindane ({gamma}-hexachlorocyclohexane) induces a biphasic inhibition of gap junction intercellular communication that is accompanied by oxidative stress. The present study investigates the hypothesis that depletion of cellular glutathione (GSH) is a mechanistic link between lindane-induced oxidative stress and inhibition of myometrial gap junctions. Exposure to 100 or 200 µM lindane rapidly (within 1 min) increased myometrial cell generation of superoxide, as measured by superoxide-inhibitable cytochrome c reduction, and superoxide production remained elevated for up to 60 min of exposure. To measure gap junction communication, Lucifer yellow dye was injected into myometrial cells and dye transfer to adjoining cells was monitored. Cells were exposed to lindane with or without GSH modulators, and dye transfer was determined at the end of a 1-h exposure to 100 µM lindane (acute phase) and 24 h after termination of lindane exposure (secondary phase). The acute phase of lindane-induced inhibition of dye transfer was prevented by GSH depletion with L-buthionine-[S,R]-sulfoximine (BSO) and enhanced by GSH augmentation with GSH monoethyl ester or L-2-oxothiazolidine-4-carboxylate (OTC). In contrast, the secondary, delayed-onset phase of lindane-induced inhibition of dye transfer was enhanced by GSH depletion with BSO and prevented by GSH augmentation with GSH monoethyl ester or OTC. Changes in cellular GSH by the pharmacological modulators were confirmed by HPLC. These results suggest that GSH is required in the acute phase but protects against the secondary phase of lindane-induced inhibition of myometrial gap junctions.

Keywords: glutathione; lindane; {gamma}-hexachlorocyclohexane; gap junctions; myometrium; oxidative stress.
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R. L. Caruso, B. L. Upham, C. Harris, and J. E. Trosko
Biphasic Lindane-Induced Oxidation of Glutathione and Inhibition of Gap Junctions in Myometrial Cells
Toxicol. Sci., August 1, 2005; 86(2): 417 - 426.
[Abstract] [Full Text] [PDF]


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