Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters postnatal T cell phenotypes and T cell function and exacerbates autoimmune lupus in 24-week-old SNF1 mice

• Published in: Birth defects research. A Clinical and molecular teratology 2009-10, Vol.85 (10), p.828-836
• Main Authors: Mustafa, Amjad, Holladay, Steven D., Goff, Matthew, Witonsky, Sharon, Kerr, Richard, Weinstein, Danielle A., Karpuzoglu-Belgin, Ebru, Gogal Jr, Robert M.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - immunology; Autoimmune Diseases - physiopathology; autoimmunity; Body Weight - drug effects; Cell Differentiation - drug effects; Cytokines - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Immunohistochemistry; Lupus Nephritis - immunology; Lupus Nephritis - physiopathology; Male; Mice; Organ Size - drug effects; Polychlorinated Dibenzodioxins - toxicity; Pregnancy; prenatal exposure; SNF1mouse; T cells; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; TCDD
• ISSN: 1542-0752; 1542-0760
• DOI: 10.1002/bdra.20603

BACKGROUND: Untreated, more than 95% of female SWR x NZB: F1 (SNF1) mice spontaneously develop a fatal lupus‐like glomerulonephritis by 8 months‐of‐age, while disease onset in males is much slower. METHODS: Timed‐pregnant SNF1 mice (10 per treatment) were exposed to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) on gestational day (GD) 12 by oral maternal gavage with 0, 40, or 80 μg/kg TCDD. RESULTS: Offspring of the TCDD‐exposed dams showed numerous alterations in T lineage cells at 24 weeks‐of‐age. Females but not males showed decreased CD4+8+ and increased CD4−8− thymocytes. Females also showed increased autoreactive CD4+Vβ17a+ axillary and inguinal lymph node T cells. Concanavalin A–stimulated splenocytes from prenatal TCDD‐treated mice produced decreased interleukin 17 (IL‐17) in the females while males showed increased IL‐2 and IFN‐γ, and diminished IL‐4. Mitogen‐stimulated pan‐lymphoproliferative responses were significantly increased across sex by TCDD. Anti‐IgG and anti‐C3 immune complex deposition in kidneys was present in the males after TCDD, and visibly worsened in females. CONCLUSIONS: Developmental TCDD exposure can permanently alter T lymphopoiesis in autoimmune‐prone SNF1 mice. The alteration profile is beyond the classic immune suppression response, to also include exacerbation and induction of a lupuslike autoimmune disease. Birth Defects Research (Part A) 2009. © 2009 Wiley‐Liss, Inc.