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，很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至关重要的作用，这使得神经系统容易受到这些常见化学物质的影响。两种主要的内分泌干扰物，邻苯二甲酸酯和双酚A (BPA)，已知会破坏性腺激素和甲状腺功能。这两种化学物质都是该提案使用啮齿动物模型的重点。接触邻苯二甲酸酯和双酚a会导致体重增加，而高脂肪饮食会加剧体重增加。高脂肪饮食本身就会干扰啮齿动物和人类儿童的认知能力。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结合，对认知行为和大脑中对这种行为很重要的神经区域（如大脑皮层）尤其有害。

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.