Project 3: Endocrine Disruptors and Diet: Effects on the Developing Cortex

内分泌干扰物是一种可以干扰荷尔蒙功能的化学物质，许多都存在于广泛使用的消费品中。荷尔蒙在神经系统的形成中起着关键作用，这使得它很容易受到这些常见化学物质的影响。内分泌干扰物的两个主要例子，邻苯二甲酸酯和双酚A(BPA)，已知可以扰乱性腺类固醇和甲状腺功能。这两种化学物质都是这项使用啮齿动物模型的提案的重点。随着邻苯二甲酸盐和双酚A的摄入，体重会增加，这种体重增加会因高脂肪饮食而加剧。高脂肪饮食本身就会干扰啮齿动物和人类儿童的认知。双酚A和邻苯二甲酸盐，以及高脂肪饮食，都会增加氧化应激和炎症，这些环境因素可能会产生表观遗传效应。我们假设，在发育过程中暴露于内分泌干扰物和高脂肪饮食的组合将对认知行为和大脑中对这种行为重要的神经区域特别有害，例如大脑皮层。 实验设计要求暴露在邻苯二甲酸盐混合物或双酚A中，同时或不同时进行高脂肪饮食。这两个目标针对的是发展过程中的两个不同时期。目的1研究在神经系统快速变化的出生前和出生后发育过程中暴露后的长期影响。目的2研究青春期的暴露，这是神经系统最后生长和修剪发生的时间，特别是在大脑皮层的前额叶区域。这两个目标的终点都将是神经元的数量、胶质细胞的数量和类型，包括小胶质细胞(随着炎症而增加)和通过免疫标记内侧前额叶皮质的酪氨酸羟基酶的多巴胺能神经支配。认知测试将包括物体识别和维度内和维度外的转换。随之而来的是体重和脂肪成分的测量，以及这些标记物中氧化应激、炎症和表观遗传变化的指数。

Endocrine disruptors are chemicals that can interfere with hormonal functions and many are found in widely used consumer products. Hormones play a critical role in the formation ofthe nervous system, which makes it vulnerable to these common chemicals. Two ofthe major examples of endocrine disruptors, the phthalates and bisphenol A (BPA), are known to disrupt both the gonadal steroids and thyroid function. Both chemicals are the focus of this proposal using a rodent model. Increases in body weight are found with exposures to the phthalates and BPA, and this weight gain is exacerbated by high fat diets. High fat diets alone interfere with cognition in both rodents and human children. BPA and the phthalates, as well as high fat diets, all increase oxidative stress and inflammation, and these environmental factors can have epigenetic effects. We hypothesize that the combination of the exposure to endocrine disruptors and a high fat diet during development will be especially pernicious for cognitive behavior and the neural regions of the brain that are important for this behavior, such as the cerebral cortex. The experimental design entails exposure to either a phthalate mixture or BPA with or without a concurrent high fat diet. Two different times during development are targeted in the two Aims. Aim 1 examines the long-term effects after exposure during pre- and post-natal development when the nervous system is rapidly changing. Aim 2 examines exposure during adolescence, a time when the final growth and pruning ofthe nervous system occurs, especially in the prefrontal area of the cerebral cortex. The end point for both of these aims will be the number of neurons, the number and types of glia including microglia (which increase with inflammation) and dopaminergic innervation through immunolabeling of tyrosine hydroxylase in the medial prefrontal cortex. Tests of cognition will include object recognition and intra- and extra-dimensional shifts. There will be accompanying measurements of body weight and fat composition and indices of oxidative stress, inflammation and epigenetic changes in these markers.