Effect of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) on maternal immune response during pregnancy

Abstract

Whether pregnancy-induced immunosuppression when combined with exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) could exacerbate immunotoxicity has not been previously investigated. The current study evaluated the immune status of C57BL/6 pregnant and virgin mice following exposure to TCDD. To this end, syngeneically pregnant or virgin female mice were injected intraperitoneally with 10 micro g/kg TCDD. Pregnancy alone significantly decreased thymic cellularity and J11d expression as well as induced changes in T-cell subsets. TCDD treatment caused significant thymic atrophy in pregnant mice as early as 48 h after exposure, but this effect was apparent in virgin mice only after 72 h. TCDD treatment also caused more marked alterations in thymic T-cell subpopulations of pregnant mice when compared to the virgin mice, with a decrease in the percentage of double-positive T cells and an increase in the percentage of single-positive (sP CD4(+) or sP CD8(+)) and double-negative T cells. Moreover, the proliferative responses of thymocytes, but not splenocytes, to mitogens were significantly altered in TCDD-treated pregnant mice when compared to the TCDD-treated virgin mice. Furthermore, no significant changes in the expression of CD4, CD8, B220 and NK1.1 markers were found in splenocytes from TCDD-treated virgin and pregnant mice. Immunization of mice with a superantigen caused a similar immunotoxic response in TCDD-treated pregnant and virgin mice with a decreased lymph node cellularity and lower percentages and cell numbers of Vbeta3(+) and Vbeta11(+) T cells. Together, the results of the current study demonstrate for the first time that pregnancy augments the sensitivity to TCDD-induced immunotoxicity in the thymus, but not in secondary lymphoid organs.

Role of Dioxin Response Element and Nuclear Factor-κB Motifs in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Regulation of Fas and Fas Ligand Expression

“…Our laboratory has previously shown that Fas/FasL-mediated apoptosis constitutes one of the key mechanisms responsible for TCDD-induced killing of T cells and immunotoxicity (Rhile et al, 1996;Kamath et al, 1997Kamath et al, , 1998Kamath et al, , 1999Camacho et al, 2001Camacho et al, , 2002Camacho et al, , 2004aCamacho et al, ,b, 2005Fisher et al, 2004). We have also demonstrated that C57BL/6 mice carrying mutations in Fas and FasL were more resistant to TCDD-mediated thymic atrophy at concentrations of Ͻ50 g/kg body weight (Rhile et al, 1996;Kamath et al, 1999;Camacho et al, 2002Camacho et al, , 2005.…”

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

“…On days 2 (GD 16) and 4 (GD 18) after DES treatment, thymic cellularity of both mothers and fetuses was determined. We had shown previously that pregnant mice exhibit a dramatic decrease in thymic cellularity compared with nonpregnant mice, and exposure to environmental contaminants, such as TCDD, further decreases their numbers (Camacho et al, 2004a). We noted that, unlike nonpregnant mice that showed ϳ250 million thymocytes/mouse (Camacho et al, 2004a), pregnant mice on GD 16 had fewer than ϳ11 million cells/mouse.…”

“…Thymocytes from mice exposed to DES or VEH were analyzed for apoptosis by using the TUNEL assay kit (Roche Diagnostics, Indianapolis, IN) as described previously (Camacho et al, 2004a(Camacho et al, ,b, 2005Singh et al, 2008). In brief, thymocytes (1 ϫ 10 6 ) from various groups of mice were cultured for 24 h in complete RPMI 1640 medium.…”

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

“…This raises an important question as to why TCDD can suppress T-cell response to an antigen in vivo, whereas it is not directly toxic to T cells in vitro. Recent studies from our laboratory shed some light in this regard by demonstrating that TCDD-induced apoptosis in thymic T cells is dependent on their interactions with thymus stromal cells (Camacho et al, 2004a(Camacho et al, ,b, 2005. We have demonstrated previously that in vivo administration of TCDD leads to up-regulation of Fas on T cells and FasL on thymic stromal cells and that interaction between these cells is critical for T cells to undergo apoptosis (Camacho et al, 2005).…”