Semester

Fall

Date of Graduation

2009

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

John B Barnett

Abstract

Cadmium (Cd) is both an environmental pollutant as well as a component of cigarette smoke. Recent data suggests increased cancer risks and increased mortality in environmentally exposed populations. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/ss-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. Our experiments were designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/ss-catenin pathways. In addition, longer term effects of prenatal Cd on the immune system were investigated. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd during pregnancy and effects on the thymus of the offspring were assessed on post-natal day 0 (PND0), while effects on the thymus and spleen were assessed on PND14 and 49. On PND0, thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways was assessed using real-time RT-PCR and western blot, respectively. On PND14 and 49, thymocyte and splenocyte phenotypes were analyzed, and cytokine production of splenic T cells was determined by ELISA. On PND0, prenatal Cd exposure increased the number of CD4+ cells and a subpopulation of double-negative cells (DN; CD4-CD8-). Shh and Wnt/ss-catenin signaling were both decreased in the thymus; however, this was not due to altered Shh and Wnt protein levels. Target genes of Shh and Wnt/ss-catenin were affected differentially among thymocyte subpopulations. On PND14 and 49, prenatal Cd exposure increased the number of DN thymocytes. In the spleen, prenatal Cd exposure had a cell type-, sex-specific effect on splenocyte phenotype and cytokine production. Collectively, these findings suggest that even very low exposure to Cd during gestation dysregulates two signaling pathways in the thymus resulting in altered thymocyte development, and this dysregulation can result in long term detrimental effects on the immune system of the offspring.

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