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

内分泌干扰物是可以干扰激素功能的化学品，许多都存在于广泛使用的消费品中。激素在神经系统的形成中起着关键作用，这使得它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，邻苯二甲酸盐和双酚A（BPA），已知会破坏性腺类固醇和甲状腺功能。这两种化学品是使用啮齿动物模型的本提案的重点。发现暴露于邻苯二甲酸盐和BPA会导致体重增加，高脂肪饮食会加剧体重增加。高脂肪饮食单独干扰啮齿动物和人类儿童的认知能力。BPA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对认知行为和对这种行为很重要的大脑神经区域（如大脑皮层）尤其有害。 实验设计需要暴露于邻苯二甲酸酯混合物或BPA，同时伴有或不伴有高脂肪饮食。两个目标针对开发过程中的两个不同时间。目的1研究在神经系统迅速变化的产前和产后发育期间暴露后的长期影响。目标2研究青春期的暴露，此时神经系统发生最终生长和修剪，特别是在大脑皮质的前额叶区域。这两个目标的终点将是神经元的数量，神经胶质细胞的数量和类型，包括小胶质细胞（其随着炎症而增加）和多巴胺能神经支配，通过免疫标记的酪氨酸羟化酶在内侧前额叶皮层。认知测试将包括物体识别和内部和外部维度的转变。将伴随测量体重和脂肪组成以及这些标记物中的氧化应激、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.