EFFECT OF MCPA 2,4 D AND BROMOXYNIL ON LUNG DEVELOPMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. North Dakota is a largely-rural state whose economy is heavily dependent on agriculture. Atrazine and the cholorophenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA) are among the most commonly applied pesticides in North Dakota, and in the United States. Chlorophenoxy herbicides are identified as endocrine disrupting (ED) chemicals, and they are believed to be responsible for feminization of animals. ED's are linked to hormonal pathways and may be toxic at levels far lower than those of traditionally used in toxicological studies. The long-term goal of this proposal is to elucidate the molecular mechanisms for the appearance of respiratory/circulatory malformations in humans due to exposure to chlorophenoxy herbicides. Our hypothesis is that exposure to chlorophenoxy compounds, by mimicking hormone action, leads to disruption of hormonal pathways involved in lung development. Subsequently, the expression of genes involved in lung development will change and ultimately will lead to circulatory/respiratory birth defects in humans. The study proposes to develop a model for embryonic lung development using Drosophila melanogaster. This study will focus on the fibroblast growth factor (FGF) pathway and its receptors; homologous of these genes are identified to be involved in human embryonic development and in tracheal development in Drosophila embryo's. Drosophila adults and embryos be exposed to chlorophenoxy herbicides and the effect on Drosophila development, tracheal development and FGF expression will be studied. Subsequently, experiments will be done in human and rodents lung cell cell lines and in an in vivo experiment in mice in order to validate effects seen in Drosophila for effects seen in humans.