Developmental exposure of SNF1 mice to TCDD induces and exacerbates postnatal autoimmune lupus-like nephritis. Mechanisms that may singly or collectively underlie this environmental chemical effect on immune development will be examined, including: impaired deletion of autoreactive T cell clones in the thymus; diminished regulatory T cells that control inappropriate responses to self antigen; the forcing of T cell differentiation into extra-thymic compartments where negative selection is inefficient; a shift in the postnatal T cell repertoire toward a T helper profile and antibody production; and inappropriate B cell activity including autoantibody production. Numbers of T cells expressing autoreactive CD4+ Vbeta 17a+ and CD3+ Vbeta 3+ TcR, and numbers of CD4+25+ regulatory T cells, in extrathymic and thymic compartments, will be followed over postnatal time in SNF1 mice (autoimmune-predisposed but TCDD insensitive) and correlated to disease progression. C57Bl/6 mice (non-autoimmune but TCDD sensitive) will be used in parallel for risk assessment considerations in individuals who may be both sensitive to TCDD and genetically predisposed to autoimmune disease. In both SNF1 and C57Bl/6 mice: Con A stimulated splenic lymphocytes will be evaluated over postnatal time to identify chemical-imprinted shifts in cytokine production that may precipitate or exacerbate the postnatal autoantibody response. Antibody level to ssDNA, dsDNA and cardiolipin will be determined for comparison to cytokine profile and T helper cell activity. A focused autoimmunity gene array consisting of appropriate response genes will be used to determine the postnatal integrity of fundamental signaling pathways, proteins and downstream targets of signal transduction pathways that mediate the immune response. A reverse transcription PCR-based differential display will be used to examine thymic MHC class I and II gene expression in SNF1 and C57Bl/6 mice, with or without TCDD exposure during gestation, as a mechanism that may impair T cell education and increase peripheral autoreactive cells. The collective experiments are designed to detect alterations in fetal immune development caused by TCDD that underlie the worsened postnatal (postpubertal) autoimmune disease caused by this chemical.
| Mustafa, A; Holladay, S D; Witonsky, S et al. (2011) A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice. Toxicology 290:156-68 |
| Holladay, Steven D; Mustafa, Amjad; Gogal Jr, Robert M (2011) Prenatal TCDD in mice increases adult autoimmunity. Reprod Toxicol 31:312-8 |
| Mustafa, Amjad; Holladay, Steven D; Goff, Matthew et al. (2009) 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. Birth Defects Res A Clin Mol Teratol 85:828-36 |
| Mustafa, A; Holladay, S D; Goff, M et al. (2008) An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD. Toxicol Appl Pharmacol 232:51-9 |
