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Antioxidants Prevent -Hexachlorocyclohexane-Induced Inhibition of Rat Myometrial Gap Junctions and Contractions¹

^a Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan 48109-2029

ABSTRACT

Lindane (-hexachlorocyclohexane) is a commonly used pesticide that bioaccumulates in mammalian adipose tissue. Lindane inhibits gap junctional intercellular communication and oscillatory contractions of pregnant rat myometrium in vitro. The present study investigated the role of oxidative stress in lindane's inhibition of myometrial function in mid-gestation pregnant rat uteri. Lucifer yellow dye was microinjected into cultured myocytes to assess gap junctional intercellular communication. Lindane exposure (100 µM) resulted in a time-dependent, biphasic inhibition of dye transfer. This pattern of inhibition was also seen upon cell exposure to the pro-oxidant, tert-butyl hydroperoxide (100 µM). Lindane's initial and secondary-onset dye transfer inhibitions were reversed by cotreatment and pretreatment with the antioxidants, -tocopherol (25–100 µM), diphenyl-1,4-phenylene diamine (10–30 µM), and superoxide dismutase (100–400 U/ml). D-mannitol (100–300 mM) also reversed lindane's initial dye transfer inhibition. Nitro blue tetrazolium reduction to formazan (measured spectrophotometrically) was elevated upon exposure of cultured cells to lindane or tert-butyl hydroperoxide, indicating the presence of reducing agents. Lipid peroxidation, assessed as thiobarbituric acid-reactive substances, was also elevated in lindane-exposed cell cultures. -Tocopherol reversed this elevation. Finally, uterine contractility was assessed by measuring isometric contractions of uterine strips hung in standard muscle baths. Pretreatment with -tocopherol prevented lindane's abolishment of uterine contractions in vitro. These data support the hypothesis that lindane inhibits uterine contractility and myometrial gap junctions by establishing an oxidative stress environment.

FOOTNOTES

First decision: 3 August 2000.

¹ This work was presented in part at the 30th Annual Meeting of the Society for the Study of Reproduction, Portland, Oregon, August 2–5, 1997, and was supported by grant ES06915 from the National Institute of Environmental Health Sciences, NIH, issued to R.L.C.; an institutional predoctoral training grant to T.R.K. (T32-HD07048) from the National Institute of Child Health and Human Development, NIH; and a predoctoral fellowship to T.R.K. from the Horace H. Rackham School of Graduate Studies, University of Michigan. Additional support was provided by the Laboratory Animal Core of the Center for the Study of Reproduction (Grant P30 HD18258 from NICHD, NIH). Contents of the work are solely the responsibility of the authors and do not necessarily represent the official views of NIEHS or NICHD.

² Correspondence: Rita Loch-Caruso, Department of Environmental Health Sciences, M 6108 School of Public Health II, 1420 Washington Heights, University of Michigan, Ann Arbor, MI 48109-2029. FAX: 734 647 9770; rlc{at}umich.edu

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