Semester

Fall

Date of Graduation

2004

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Kenneth Landreth.

Abstract

Hematotoxicity has been documented in adults exposed to high levels of organochlorine pesticides. Our studies revealed that prenatal exposure to the organochlorine pesticide heptachlor resulted in alteration of lymphocyte development, while myeloid cell development was spared. To further investigate effects of heptachlor on lymphoid cells, we evaluated direct exposure of this compound on pro-B and pre-B cells. In these studies, the pro-B cell line C1.92 and the pre-B cell line 70Z/3 demonstrated concentration-dependent decreases in proliferation following heptachlor exposure. Pro-B cell viability decreased significantly; however, pre-B cell viability was not altered. Further investigation into mechanisms of diminished cell proliferation revealed that heptachlor exposure altered nuclear factor kappa B (NF-kappaB) localization in both cell lines. Pre-B cells exposed to heptachlor differentiated and expressed surface kappa immunoglobulin light chain. This exposure correlated with increased NF-kappaB in nuclei of pre-B cells. When NF-kappaB was retained in the cytoplasm of pre-B cells in the presence of capsaicin, heptachlor exposure failed to induce kappa light chain surface expression. This further indicated heptachlor induced differentiation of pre-B cells through altered NF-kappaB signaling. Exposure of pro-B cells to heptachlor alone resulted in decreased nuclear NF-kappaB translocation, decreased phosphorylation of I-kappaB, and apoptosis of these pro-B cells. These data have allowed us to construct a working hypothesis that exposure to heptachlor alters the normal development of lymphoid cells.

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