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.
BACKGROUND
Untreated, more than 95% of female SWR x NZB: F(1) (SNF(1)) mice spontaneously develop a fatal lupus-like glomerulonephritis by 8 months-of-age, while disease onset in males is much slower.


METHODS
: Timed-pregnant SNF(1) 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 microg/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(+)Vbeta17(a+) 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-gamma, 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.
Mustafa
Amjad
A
Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University Blacksburg, Virginia, USA.
Holladay
Steven D
SD
Goff
Matthew
M
Witonsky
Sharon
S
Kerr
Richard
R
Weinstein
Danielle A
DA
Karpuzoglu-Belgin
Ebru
E
Gogal
Robert M
RM
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology*; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008181:Lupus Nephritis / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
D016207:Cytokines; D000072317:Polychlorinated Dibenzodioxins