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Acceleration of Autoimmunity by Organochlorine Pesticides in (NZB NZW)F₁ Mice

Eric S. Sobel,¹ John Gianini,¹ Edward J. Butfiloski,¹ Byron P. Croker,^2,3 Joel Schiffenbauer,^1* and Stephen M. Roberts⁴

¹Department of Medicine, and ²Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA; ³Northern Florida/Southern Georgia Veterans Health System and Laboratory Medicine Service, Gainesville, Florida, USA; ⁴Department of Physiological Sciences, J. Hillis Miller Health Science Center, University of Florida, Gainesville, Florida, USA

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects women more frequently than men. In the (NZB NZW) F₁ mouse, a murine SLE model, the presence or absence of estrogen markedly influences the rate of progression of disease. Three organochlorine pesticides with estrogenic effects were administered chronically to ovariectomized female (NZB NZW) F₁ mice, and we measured the time to development of renal disease, the principal clinical manifestation of lupus in this model. Treatment with chlordecone, methoxychlor, or o,p´-dichlorodiphenyltrichloroethane (o,p´-DDT) significantly decreased the time to onset of renal impairment, as did treatment with 17ß-estradiol used as a positive control. In an expanded study of chlordecone, we found a dose-related early appearance of elevated anti-double-strand DNA autoantibody titers that corresponded with subsequent development of glomerulonephritis. Immunohistofluorescence confirmed early deposition of immune complexes in kidneys of mice treated with chlordecone. These observations are consistent with an effect of these organochlorine pesticides to accelerate the natural course of SLE in the (NZB NZW) F₁ mouse. Although we originally hypothesized that the effect on progression of autoimmunity was due to estrogenic properties of the pesticides, autoimmune effects and estrogenicity, assessed through measurement of uterine hypertrophy, were not well correlated. This may indicate that uterine hypertrophy is a poor indicator of comparative estrogenic effects of organochlorine pesticides on the immune system, or that the pesticides are influencing autoimmunity through a mode of action unrelated to their estrogenicity. Key words: autoimmunity, chlordecone, DDT, estrogenicity, glomerulonephritis, kepone, methoxychlor, organochlorine pesticides, systemic lupus erythematosus. Environ Health Perspect 113:323-328 (2005) . doi:10.1289/ehp.7347 available via http://dx.doi.org/ [Online 2 December 2004]

Address correspondence to E.S. Sobel, University of Florida College of Medicine, 1600 SW Archer Rd., Box 100221, Gainesville, FL 32610 USA. Telephone: (352) 392-9494. Fax. (352) 392-8483. E-mail: sobeles@medicine.ufl.edu

*Current address: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, 9201 Corporate Blvd., Rockville, MD 20850 USA.

This work was supported in part by grants 1R21 ES10296 and 1 P42 ES07375 from the National Institute of Environmental Health Sciences.

The authors declare they have no competing financial interests.

Received 22 June 2004 ; accepted 2 December 2004.

Correction

Values for body weight and dosing rate for chlordecone and the dosing rates for methoxychlor and o,p´-DDT were incorrect in the "Discussion" of the original manuscript published online. They have been corrected here.