Propanil is a post-emergent herbicide that is used extensively on rice. Rice has high levels of arylamidase, which allows it to detoxify the propanil, thus, making it possible to apply this herbicide several times during a growing season and approximately 9 million pounds of propanil are used annually. Because of its high rate of use, this herbicide presents a major exposure threat to applicators, loaders, and farm families throughout the USA. We have previously shown that propanil causes reduced cytokine production when administered in vivo to mice and when added to both murine and human T cell cultures. Our data indicate that this is at least partially due to its ability to interfere with cellular signaling processes required to initiate optimal transcription. Our data shows that this results in reduced nuclear levels of at least three transcription factors, NF-AT, NF-KB and AP- 1, required for IL-2 gene transcription. Since the last submission, sufficient additional data has been collected to allow statistical analysis of the changes in these transcription factors. Of critical importance in the interpretation of these results is that in addition to the significant changes in the levels of these transcription factors is the noted change in chronology of peak production. Published data indicates that all three transcription factors must be present at the same time for optimal cytokine production 21;40;77. This proposal will investigate the mechanism of this effect on human T cells by thoroughly examining the signaling pathways required to initiate IL-2 transcription. This will be accomplished through three specific aims: 1) Determine the steps in the c-jun activation pathway that propanil affects in human T lymphocytes. 2) Determine the effect of propanil on early receptor-mediated signaling events that lead to NF-AT activation. 3) Determine the step(s) in the NFkB signaling pathway affected by propanil.
