Date of Award
Open Access Thesis
Narendra P Singh
Diethylstilbestrol (DES) is a synthetic compound and considered as an endocrine disruptor that interferes with the normal development of human organs and even immune tissues. DES has been investigated for its immunosuppressive effects, thymic atrophy, and various types of cancer including breast cancer, ovarian cancer, uterine cancer, etc. In this study, we investigated DES regulated mechanisms in T cells and examined whether DES exposure of T cells leads immune suppression and affects immune functions. To this end, we investigated the effect of DES on T cells in vitro and specifically examined DES-induced apoptosis in T cells, expression of genes involved in apoptosis, and differentiation of T helper cells in vitro. We observed significant increase in apoptosis in activated T cells in dose-dependent manner in vitro. Upon examination of FasL expression in activated T cells, there was a significant increase in FasL expression in activated T cells post DES treatment. Furthermore, upon examination of microRNA (miR) profile in activated T cells, there was a dysregulation in a large number of miRs by DES. Out of a total of 885 miRs screened, there were 217 miRs showing more than 1.5 fold and 101 miRs showing 2.0 fold or more differential expression in DES group when compared to vehicle-treated group. Next, the immunosuppressive effect of DES was tested using an mouse model of delayed type hypersensitivity (DTH). Interestingly, DES treatment decreased the DTH responses and reversed the inflammation triggered by methylated bovine serum albumin (mBSA). Also, there was a significant increase in regulatory T (Tregs) cells but suppression of both Th1 and Th17 cells in mice that received mBSA associated with DES [mBSA+DES] treatment when compared to mBSA associated with vehicle (VEH) [mBSA+VEH] treatment. Taken together, the results obtained from this study demonstrate that DES-mediated immune suppression may be due to mechanisms involving apoptosis, dysregulation in gene expression, changes in miR profile and regulation of T cell differentiation.
Menard, M.(2014). Diethylstilbestrol (DES) mediates immune suppression via modulation of microRNA expression in mice. (Master's thesis). Retrieved from http://scholarcommons.sc.edu/etd/2756