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

Abstract

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.

Figure 1

The kidneys from 24-week-old SNF₁ mice that were prenatally exposed to 0, 40 or 80 μg/kg TCDD were collected, fixed, sectioned and stained with FITC-labeled anti-IgG and anti-C3. The above are representative images of kidneys stained with FITC-anti-IgG based on treatment and sex. The data are based on 5 mice /treatment/sex (*= p ≤ 0.05, Dunnett's test).

Figure 2

The lymphoproliferative responses of cultured splenocytes in 24-week-old SNF₁ mice exposed prenatally to 0, 40 or 80 μg/kg TCDD. Splenocytes were exposed to Con A or P/I for 48 h or 72 h. Values are reported as mean Δ specific absorbance ± SEM. The results are based on 5 mice/treatment/sex (*= p ≤ 0.05, Dunnett's test).

Figure 3

Supernatants were collected from splenocytes, of 24-week-old mice that were prenatally exposed to 0, 40 or 80 μg/kg TCDD, and cultured for 48 h with Con A (10 μg/mL). The levels of IL-2, IL-4, IL-10, IL-12, IL-17 and INF-γ were determined using commercially available murine cytokine ELISA kits. The data are presented as mean ± SEM. The results are based on 5 mice/treatment/sex (*= p ≤ 0.05, Dunnett's test).