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ToxSci Advance Access originally published online on June 19, 2007
Toxicological Sciences 2007 99(1):141-152; doi:10.1093/toxsci/kfm137
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Acceleration of Autoimmunity by Organochlorine Pesticides: A Comparison of Splenic B-Cell Effects of Chlordecone and Estradiol in (NZBxNZW)F1 Mice

Fei Wang*,1, Stephen M. Roberts*,{dagger},2, Edward J. Butfiloski{ddagger}, Laurence Morel§ and Eric S. Sobel{ddagger}

* Department of Pharmacology and Therapeutics {dagger} Department of Physiological Sciences {ddagger} Department of Medicine § Department of Pathology, Immunology and Laboratory Medicine, J. Hillis Miller Health Science Center, University of Florida, Gainesville, Florida 32610

2 To whom correspondence should be addressed at Center for Environmental and Human Toxicology, Box 110885, University of Florida, Gainesville, FL 32611. Fax: (352) 392-4707. E-mail: smr{at}ufl.edu.

Received March 22, 2007; accepted May 17, 2007


  Abstract

The weakly estrogenic organochlorine pesticide chlordecone can accelerate the development of systemic lupus erythematosus (SLE) in ovariectomized (NZB x NZW)F1 mice, with a shortened time to appearance of autoantibodies and disease similar to that produced by treatment with the sex hormone 17ß-estradiol (E2). It is unclear whether chlordecone and E2 share the same pathways in mediating this effect. The effects of chlordecone and E2 treatment on splenic germinal center (GC) and marginal zone B cells were examined. Both chlordecone and E2 activated splenic B cells and enhanced GC reactions, as shown by upregulated protein expression of GL7, CXCR5, and CXCR4. Both treatments increased B-cell bcl-2 and shp-1 gene expression and enhanced ICAM-1 and VCAM-1 protein levels in GC B cells. Chlordecone reduced total B cell and GC B-cell apoptosis without affecting proliferation, another feature shared by E2 treatment. However, chlordecone treatment did not alter the composition of splenic B-cell subsets in marked contrast to the decrease in transitional B cells and increase in marginal zone B cells seen in E2-treated mice. The differences in effects between chlordecone and E2 indicate that chlordecone is not functioning simply as an estrogen mimic with respect to effects on the immune system. Similarities in the effects of chlordecone and E2 on specific immune functions, such as diminished apoptosis in GC B cells, may provide valuable clues regarding key events in the acceleration of autoimmunity by E2, chlordecone, and other agents.

Key Words: autoimmunity; estrogen; chlordecone; spleen; splenocytes; systemic lupus erythematosus.

1 Present address: Global Safety and the Environment, Merck & Co., Inc., Whitehouse Station, NJ 08889.


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