ToxSci Advance Access originally published online on August 10, 2009
Toxicological Sciences 2009 112(1):133-143; doi:10.1093/toxsci/kfp177
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Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts B-Cell Lymphopoiesis and Exacerbates Autoimmune Disease in 24-Week-Old SNF1 Mice
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* Center for Molecular Medicine and Infectious, Diseases, Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060-0442
Department of Anatomy and Radiology, College of Veterinary Medicine, University of Georgia, Athens 30602-7382
Department of Large Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060-0442
Department of Biomedical Sciences, Virginia College of Osteopathic Medicine, Blacksburg, Virginia 24061-0442
¶ Institute of Gene and Transplantation, Baskent University, Ankara, Turkey 30602-7382
1 To whom correspondence should be addressed at H343, College of Veterinary Medicine, 501 DW Brooks Drive, University of Georgia, Athens, GA 30602-7382. Fax: (706) 542-0051. E-mail: rgogal{at}uga.edu.
Received April 30, 2009; accepted July 30, 2009
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Abstract |
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Female SNF1 hybrid mice spontaneously develop an immune complex–mediated glomerulonephritis as early as 24 weeks of age, whereas the disease onset in males is much slower. Further, a rise in concentration of glomerulus-specific autoantibodies via autoreactive B cells is critical to progression of the disease in this strain. Environmental factors contributing to the onset or degree of such autoimmunity are of interest yet poorly understood. In the present study, time-pregnant SWR x NZB dams (10/treatment) were gavaged on gestational 12 with 40 or 80 mg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the SNF1 offspring were evaluated at 24 weeks of age. Bone marrow B220lowCD24–AA4.1+ committed B lineage progenitors were increased in female offspring by TCDD, however, committed progenitors and pro-B cells were decreased in males. Splenic marginal zone B cells (CD21hiCD24low–int) were decreased and follicular B cells (CD21intCD24low) were increased across sex by prenatal TCDD, whereas transitional-2 B cells (CD21intCD24hi) and (CD23low–int CD1low–int) were decreased in males only. Antibodies to double-stranded DNA were significantly increased across sex by TCDD. Anti-IgG and anti-C3 immune complex renal deposition was visibly worsened in females, and present in TCDD-treated males. These data suggest that developmental exposure to TCDD permanently and differentially alters humoral immune function by sex, and exacerbates a type III hypersensitivity lupus-like autoimmune disease in genetically predisposed mice.
Key Words: TCDD; prenatal exposure; autoimmunity; lupus; SNF1 mouse.