Estrogens have widespread applications in health and disease. Postmenopausal women are treated with estrogen replacement therapy to relieve them of the menopausal symptoms. Between 1940-1975, an estimated 5-10 million Americans received diethylstilbestrol (DES), a synthetic estrogen, during pregnancy or were exposed to the drug in utero. Exposure to DES has been associated with an increased risk for breast cancer in """"""""DES mothers"""""""" and a lifetime risk of cervicovaginal cancers in """"""""DES daughters"""""""". Exposure to DES has also been linked to a wide range of abnormalities in """"""""DES sons and daughters"""""""" including immune system disorders such as increased incidence of autoimmunity, cancer and certain infections. Furthermore, a number of xenoestrogens which include environmental estrogens and phytoestrogens have been identified which bind estrogen receptors (ERs) and mediate activity similar to physiological estrogens. Thus, research on DES may serve as a template to study a growing list of endocrine disruptors. Studies from our lab demonstrated for the first time that prenatal and postnatal exposure to estradiol (E2) and DES can induce apoptosis in thymocytes, alter the expression of T cell receptor and CD molecules, and modulate positive and negative selection of T cells. In the current study, we will test the central hypothesis that prenatal exposure to DES alters the positive and/or negative selection of T cells in the thymus leading to generation of skewed T cell repertoire with enhanced reactivity towards self antigens and decreased response against non-self antigens.
In aim# 1, we will investigate whether the regulation of Fas and Fas ligand genes involves estrogen responsive elements (ERE) and other transcription factors.
Aim# 2 will test if prenatal exposure to DES alters positive and negative selection of T cells in the thymus and thereby skewing the immune responsiveness of mature T cells to self rather than non-self antigens.
Aim# 3 will investigate the role of ERa in DES induced apoptosis and development of autoimmunity. Also, the role of T cell-stromal cell interactions in DES-induced thymocyte apoptosis will be studied.
In Aim# 4, the mechanism by which prenatal DES exposure leads to increased susceptibility to autoimmune disease postnatally will be tested. Together, the studies proposed should provide novel information on the mechanism by which prenatal exposure to DES leads postnatally to increased susceptibility to autoimmunity and cancer and to development of potential approaches to prevent such immunotoxicity.
There has been a high incidence of cancers as well as autoimmune diseases observed in women who were prescribed during pregnancy, a synthetic estrogen known as diethylstilbestrol, as well as in their sons and daughters. Postmenopausal women administered estrogens in hormone replacement therapy, as well as, several chemicals found in the environment and foods act as estrogens causing significant health problems. Thus, our studies are aimed at providing insights into the mechanism by which estrogens mediate their toxic effects on the immune system, thereby leading to the development of strategies for their prevention and treatment.
|Bam, Marpe; Yang, Xiaoming; Zhou, Juhua et al. (2016) Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients. J Neuroimmune Pharmacol 11:168-81|
|Yang, Xiaoming; Bam, Marpe; Nagarkatti, Prakash S et al. (2016) RNA-seq Analysis of Î´9-Tetrahydrocannabinol-treated T Cells Reveals Altered Gene Expression Profiles That Regulate Immune Response and Cell Proliferation. J Biol Chem 291:15460-72|
|Bam, Marpe; Yang, Xiaoming; Zumbrun, Elizabeth E et al. (2016) Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation. Sci Rep 6:31209|
|Sido, Jessica M; Jackson, Austin R; Nagarkatti, Prakash S et al. (2016) Marijuana-derived Î”-9-tetrahydrocannabinol suppresses Th1/Th17 cell-mediated delayed-type hypersensitivity through microRNA regulation. J Mol Med (Berl) 94:1039-51|
|Singh, Narendra P; Singh, Udai P; Rouse, Michael et al. (2016) Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA. J Immunol 196:1108-22|
|Chandrashekaran, Varun; Das, Suvarthi; Seth, Ratanesh Kumar et al. (2016) Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta 1862:32-45|
|Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2016) Production of endocannabinoids by activated TÂ cells and BÂ cells modulates inflammation associated with delayed-type hypersensitivity. Eur J Immunol 46:1472-9|
|Elliott, David M; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2016) 3,39-Diindolylmethane Ameliorates Staphylococcal Enterotoxin Bâ€“Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells. J Pharmacol Exp Ther 357:177-87|
|Guan, Hongbing; Singh, Udai P; Rao, Roshni et al. (2016) Inverse correlation of expression of microRNA-140-5p with progression of multiple sclerosis and differentiation of encephalitogenic T helper type 1 cells. Immunology 147:488-98|
|Sido, Jessica Margaret; Yang, Xiaoming; Nagarkatti, Prakash S et al. (2015) Î”9-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid-derived suppressor cell activation via STAT3/S100A8. J Leukoc Biol 97:677-88|
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