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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 北达科他州是一个以农村为主的州，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。氯苯氧基除草剂被确定为内分泌干扰(ED)化学物质，它们被认为是导致动物雌性化的原因。ED与荷尔蒙途径有关，其毒性水平可能远远低于毒理学研究中传统使用的水平。 这项建议的长期目标是阐明由于接触氯苯氧基除草剂而导致人类出现呼吸/循环畸形的分子机制。我们的假设是，暴露在氯苯氧基化合物中，通过模仿荷尔蒙的作用，导致参与肺发育的荷尔蒙途径中断。随后，参与肺发育的基因的表达将发生变化，最终将导致人类的循环/呼吸系统出生缺陷。 这项研究建议开发一个利用黑腹果蝇进行胚胎肺发育的模型。本研究将重点研究成纤维细胞生长因子途径及其受体；这些基因的同源基因被鉴定为参与人类胚胎发育和果蝇胚胎的气管发育。 将果蝇成虫和胚胎暴露在氯苯氧基除草剂中，并研究其对果蝇发育、气管发育和成纤维细胞生长因子表达的影响。随后，将在人类和啮齿动物肺细胞系中进行实验，并在小鼠身上进行体内实验，以验证在果蝇中看到的效果与在人类中看到的效果。

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.