Journal Article

Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin Disrupts B-Cell Lymphopoiesis and Exacerbates Autoimmune Disease in 24-Week-Old SNF<sub>1</sub> Mice

Amjad Mustafa, Steven D. Holladay, Sharon Witonsky, Kurt Zimmerman, Christopher M. Reilly, D. Phillip Sponenberg, Danielle A. Weinstein, Ebru Karpuzoglu and Robert M. Gogal

in Toxicological Sciences

Volume 112, issue 1, pages 133-143
Published in print November 2009 | ISSN: 1096-6080
Published online August 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp177
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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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 × 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 B220lowCD24AA4.1+ 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.

Keywords: TCDD; prenatal exposure; autoimmunity; lupus; SNF1 mouse

Journal Article.  5764 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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