This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The Study and Characterization of Xenoestrogen Effects on TCell Mediated ImmunityEndogenous estrogens, androgens, and prolactin contribute to the sexual dichotomy of immune responses and the female preponderance of autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA). Epidemiological evidence in humans and hormonal manipulation of immune/autoimmune responses in animals supports this concept (1-6). Several environmental, hormonally active endocrine-disrupting compounds exist, are superimposed upon the endogenous pituitary-gonadal axis, and may contribute to the incidence or development of immune disease. However, investigations have typically focused on classic endocrinological and not immunological target organ responses. The majority of studies have examined traditional endocrine targets such as breast, uterus, ovary, testes, reproductive capacity and function, or teratogenicity whereas few studies, exclusive of those with TCDD, have investigated low-dose effects of xenoestrogens on immune function, specifically adaptive T cell mediated immunity (7-18). Xenoestrogenic compounds such as coumestrol (a phytoestrogen), bisphenol A (BPA a plastic monomer), and o, p'-dichlorodiphenyltrichloroethane (DDT an organochlorine) are representative environmental endocrine disrupters from different categories that can be classified as xenoestrogens and are known to have some immunoendocrine actions (refs. 717; Table 1). Investigation of xenoestrogen immunomodulation may be critical to understanding potential low dose adverse/no adverse effects on development of immune or autoimmune disorders, resistance to infection, cancer immune surveillance, or cell cycle/cell survival abnormalities that could lead to lymphoid malignancies. In this application, we propose to further develop and characterize in vitro immunobiological systems for studying the nature of the dose and exposure time relationship to low dose adverse effects on T-cell mediated immunity, focusing on molecular markers of T cell function and survival. We hypothesize that xenoestrogens suppress lymphoproliferation and increase lymphocyte apoptosis through suppression of bcl-2 and cyclin A and stimulation of p53; suppress IL-2 and stimulate IL-4 or IL-10 through effects on nuclear transcription. The overall goal of this proposal is to characterize the effects and delineate xenoestrogen mechanisms of action on T lymphocyte immune responses.
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