Understanding Complex Toxicological Mechanisms of Glyphosate and Mechanism-Sharing Environmental Chemical Mixtures

孟山都公司生产的RoundUp中的活性成分Glycoprotein是最常用的 美国农业、工业和家庭环境中使用的农药有1.8 - 1.85亿磅， 2007年，美国。虽然草甘膦暴露与不良健康影响有关，但令人惊讶的是， 关于长期健康影响和相关潜在毒性的全部机制信息 草甘膦暴露。了解草甘膦如何与哺乳动物体内的生物系统相互作用 研究草甘膦对人体的长期毒性作用及其机制是十分必要的 健康该项目将应用创新的化学技术来绘制直接的蛋白质组范围 草甘膦及其潜在活性代谢物的体内靶点，以及研究 共同暴露于草甘膦和通过重叠机制起作用的化学混合物。这里我们 将使用一种创新的化学蛋白质组学策略，称为基于反应性的蛋白质谱分析（RBPP）， 使用基于反应性的化学探针来识别复杂蛋白质组中的超反应蛋白热点， 绘制草甘膦的直接蛋白质组靶点。使用RBPP平台，我们发现草甘膦 以及几种高使用率的环境化学物质通常抑制几种代谢 参与脂肪酸降解和代谢的酶。我们假设累积暴露于 草甘膦和其他通常抑制脂肪酸降解酶的环境化学品将 直接引起体内叠加或协同脂质失调、组织肥胖和血清血脂异常， 小鼠我们建议应用创新的化学蛋白质组学平台来绘制蛋白质组范围的靶点， 草甘膦揭示了这种广泛使用和有争议的除草剂的新毒理学机制， 特别侧重于了解接触草甘膦和其他化学品， 营养暴露可协同影响脂肪代谢。

Glyphosate, the active ingredient in RoundUp produced by Monsanto, is the most commonly used pesticides in the US across agricultural, industrial, and home settings with 180-185 million pounds used in the US in 2007. \ While glyphosate exposure has been linked to adverse health effects, there is a surprising lack of mechanistic information concerning the full scope of long-term health effects and potential toxicities associated with glyphosate exposure. Understanding how glyphosate interacts with biological systems in vivo in mammals is absolutely necessary to assess the prolonged effects and mechanism of toxicity of glyphosate on human health. This project will apply innovative chemical technologies to map the direct proteome-wide targets of glyphosate and its potentially reactive metabolites in vivo, as well as investigate the effects co-exposures to glyphosate and chemical mixtures that act through overlapping mechanisms. Here, we will use an innovative chemoproteomic strategy termed reactivity-based protein profiling (RBPP), which uses reactivity-based chemical probes to identify hyper-reactive protein hotspots in complex proteomes, to map direct proteome-wide targets of glyphosate. Using the RBPP platform, we have found that glyphosate as well as several high usage environmental chemicals of concern commonly inhibit several metabolic enzymes involved in fatty acid degradation and metabolism. We hypothesize that cumulative exposure to glyphosate and other environmental chemicals that commonly inhibit fatty acid degradation enzymes will directly cause additive or synergistic lipid dysregulation, tissue adiposity, and serum dyslipidemia in vivo in mice. We propose to apply innovative chemoproteomic platforms to map proteome-wide targets of glyphosate to reveal novel toxicological mechanisms of this widely used and controversial herbicide, with a particular focus on understanding how exposure to glyphosate and other chemical and nutritional exposures may synergize to impact fat metabolism.