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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 北达科他州是一个大面积的农村州，其经济严重依赖农业。 阿特拉津和氯苯氧基除草剂2，4-二氯苯氧基乙酸（2，4-D）、4-氯-2-甲基苯氧基乙酸（MCPA）是北达科他州和美国最常用的杀虫剂。氯苯氧基除草剂被认为是内分泌干扰（艾德）化学品，并且被认为是导致动物雌性化的原因。 艾德与激素途径有关，其毒性水平可能远低于毒理学研究中传统使用的水平。 该提案的长期目标是阐明由于暴露于氯苯氧基除草剂而导致人类呼吸/循环畸形的分子机制。 我们的假设是，暴露于氯苯氧基化合物，通过模仿激素的作用，导致参与肺发育的激素途径中断。 随后，参与肺发育的基因的表达将发生变化，最终导致人类的循环/呼吸系统出生缺陷。 本研究拟利用果蝇建立胚胎肺发育模型。本研究将集中在成纤维细胞生长因子（FGF）途径及其受体，这些基因的同源性被确定为参与人类胚胎发育和果蝇胚胎气管发育。 将果蝇成虫和胚胎暴露于氯苯氧除草剂，并研究其对果蝇发育、气管发育和FGF表达的影响。 随后，将在人类和啮齿类动物肺细胞系中进行实验，并在小鼠体内实验中进行实验，以验证在果蝇中观察到的作用对人类的影响。

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.