Date of Graduation

1997

Document Type

Thesis

Abstract

Propanil (3,4-dichloropropionanilide) is a herbicide that is used for post-emergence control of weeds on rice, wheat, and potato production in the United States. The first hypothesis of our study is: propanil significantly inhibits cytokine production by macrophages which may contribute to its overall immunotoxicity. We demonstrate that i.p. propanil exposure significantly inhibited IL-6, TNF-{dollar}\\alpha{dollar} and IL-1{dollar}\\beta{dollar} production by macrophages. Acute oral exposure with propanil demonstrates that both 3 and 7 day post-exposure cytokine production by macrophages was reduced. However, only 7 day post-exposure with the primary metabolite of propanil, 3,4-dichloroaniline (DCA), resulted in the inhibition of cytokine production. Therefore, we conclude that the immediate inhibitory effects (3 day post-exposure) on cytokine production are due to the direct toxicity of propanil, while the delayed inhibitory effects (7 day post-exposure) are caused by the further breakdown of DCA. The in vitro propanil or DCA exposure confirms this conclusion by showing that it took 10 times the concentration of DCA than that of propanil to inhibit cytokine production at a similar degree. Since IL-6, TNF-{dollar}\\alpha{dollar} and IL-1{dollar}\\beta{dollar} are important multifunctional proinflammatory cytokines involved in generating both humoral and cell-mediated immune response, the reduction of all three cytokines by propanil treatment may contribute to the previously demonstrated overall immunotoxicity of propanil. The second hypothesis of our study is: propanil affects macrophage cytokine production at the level of pre-transcription. Northern blot analysis shows that propanil reduces IL-6 and TNF-{dollar}\\alpha{dollar} production at the message level. Coincident reductions in protein and message levels point to a pre-translational target for propanil. The mRNA stability studies demonstrate that the degradation rates for IL-6 and TNF-{dollar}\\alpha{dollar} mRNA were not affected. However, the release of intracellular Ca{dollar}\\sp{lcub}2+{rcub}{dollar} in LPS-activated macrophages was completely abrogated by propanil. Moreover, the level of inositol-1,4,5-trisphosphate (IP{dollar}\\sb3{dollar}) was increased in propanil-treated macrophages. Structural comparison of propanil and IP{dollar}\\sb3{dollar} molecules using Alchemy{dollar}\\sp{lcub}\\rm TM{rcub}{dollar} computer program demonstrates sufficient similarities between the two molecules. Thus, we conclude that the action of IP{dollar}\\sb3{dollar} is blocked by propanil leading to the abrogation of intracellular Ca{dollar}\\sp{lcub}2+{rcub}{dollar} influx, as a result, the LPS-induced cytokine production is inhibited. The proposed model of propanil's action may account for the broad immunotoxicity of propanil, since IP{dollar}\\sb3{dollar} is a common signal used by many different types of cells in response to various extracellular stimuli. Taken together, our findings provide an explanation for the propanil-induced overall immunotoxicity at the cellular level, and a mechanism for propanil's action at the molecular level.

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