Wei Zhao

Date of Graduation

1996

Document Type

Thesis

Abstract

Propanil is a post-emergent herbicide which has been extensively used for control of weeds in rice and wheat field. Acute exposure to propanil central nervous system depression, loss of a righting reflex, and cyanosis. The immunotoxic effects of propanil on animals include reduction of thymus weight and cellularity with increase of spleen weight and cellularity, inhibition of humoral and cell-mediated immune response and alteration NK cell activity and macrophage cytotoxicity. The overall goal of this project is to investigate the mechanism and recovery of propanil induced thymic atrophy and the effect of propanil on T cell cytokine production. Using cell surface staining with flow cytometry, we found that the thymic atrophy was characterized by a depletion of CD4{dollar}\\rm\\sp+CD8\\sp+{dollar} population. No atrophy was observed in adrenalectomized, propanil-treated mice, suggesting that the immunotoxic effect of propanil on thymus appears to be mediated, in part, by endogenous glucocorticoids. DNA staining data showed higher percentage of proliferating CD4{dollar}\\rm\\sp+CD8\\sp+{dollar} thymocytes 4 days after exposure. Thus, recovery of the thymus occurs following increases in thymocyte proliferation, most notably the immature CD4{dollar}\\rm\\sp+CD8\\sp+{dollar} thymocytes. We used both in vivo and in vitro models to study the effect of propanil on T cell cytokine production. In vivo exposure to propanil selectively inhibits the production of IL-2, 6, GM-CSF, and IFN-{dollar}\\gamma.{dollar} In vitro exposure model demonstrated that splenocytes produce significant less IL-2, IL-6, IFN-{dollar}\\gamma{dollar} and GM-CSF after propanil treatment. We then used a T cell line, EL-4 cells to further investigate the mechanism of propanil caused inhibition of IL-2 production at protein, message and gene expression levels. Quantitave Northern blot analysis of IL-2 mRNA showed a dose-dependent decrease in propanil treated EL-4 cells upon PMA stimulation. To determine if the reduced message production was due to reduced signaling or message stability, nuclear run-on and mRNA stability assays were performed. Nuclear run on assays revealed that the transcription rate of the IL-2 gene was decreased by approximately 50% in the presence of 0.02 mM propanil. IL-2 message stability assays also revealed a reduction in message stability. Taken together, these results suggest that propanil inhibits IL-2 production at both transcriptional and post-transcriptional levels.

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