A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice

Abstract

We recently observed an autoimmune profile in 24-week-old C57BL/6 mice that received a 2.5 or 5.0 μg/kg mid-gestation dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Mustafa et al., 2008). The clinical signs were consistent with a lupus-like syndrome and included: increased autoantibody levels, renal IgG and C3 immune complex deposition with associated inflammation, and increased peripheral Vβ+ T cells. No studies currently exist following the progression of such disease into middle or advanced ages, when human autoimmune diseases may manifest. Therefore in the present study, littermates of mice from the previous 24 week prenatal TCDD study were allowed to age to 48 weeks, considered early geriatric in mice. Similarities and differences in the disease profile based on age and sex were observed. Peripheral autoreactive Vβ+ T cells were increased in both sexes at 48 weeks, in contrast to males only at 24 weeks. Activated T cells from 48-week-old prenatal TCDD females over-produced the proinflammatory cytokine IFN-γ while males over-produced IL-10, effects again not seen at 24 weeks. Splenic transitional-2 B cells (CD21intCD24hi) were increased in males while transitional-1 B cells (CD23neg CD1neg) were increased in females at 48 weeks. Autoantibodies to cardiolipin and CD138+ spleen plasma cells were significantly increased in the aged males but not females. Anti-IgG and anti-C3 immune complex renal deposition were also significantly increased in the prenatal TCDD males but not females. These selective changes in the aged male mice may be noteworthy, in that the prevalence of SLE in humans shifts dramatically toward males with aging. The collective findings in aged mice suggest that prenatal TCDD permanently biases the postnatal immune response in C57BL/6 mice toward autoimmunity, and support a significant B cell component to the induced renal autoimmune disease.

Fetal exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin transactivates aryl hydrocarbon receptor‐responsive element III in the tyrosine hydroxylase immunoreactive neurons of the mouse midbrain

“…There have been numerous reports on the adverse effects of TCDD on the reproductive system (Naville et al, 2011;Simanainen et al, 2004), endocrine system (Ahmed, 2011;Piaggi et al, 2007), immune system (Mustafa et al, 2011;Lu et al, 2010), and so on. However, the mechanisms of TCDD toxicity have not been well studied, especially in the central nervous system.…”

Gender differences in autoimmunity associated with exposure to environmental factors

“…There is some indication that TCDD can promote autoimmunity when exposure occurs during fetal or early neonatal development. C57BL/6 mice that received TCDD mid-gestation showed signs of male biased autoimmunity with increased autoantibodies and immune deposits in 48 week old male mice compared to females [136]. These observations suggest that mid-gestation exposure to TCDD may provide a model for the age related increase of SLE in males.…”

Endocrine Disrupting Chemicals and Type 1 Diabetes

“…However, the effect of TCDD on the immune system is complex. In mice, exposure to TCDD during in utero critical developmental stages promoted the development of autoimmune diseases later in life [81] and probably T1D could be included among them.…”