Prenatal Sex Steroids, Bisphenol A, Phthalates, and Sexually Dimorphic Behaviors

描述(由申请人提供) 胎儿的大脑是特别敏感的，环境中的化学物质暴露和内分泌系统的失调可能会增加不良神经行为结果的风险，如自闭症、注意力缺陷/多动障碍或抑郁症。在Bellinger博士和Hauser博士的指导下，这项培训和研究计划将以Braun博士作为环境流行病学家的专业知识为基础，为他的职业生涯做好准备，研究内分泌干扰物(EDCs)及其对激素系统和儿童神经发育的影响。布劳恩博士从未接受过这些领域的正式培训，很少有研究人员拥有这种独特的跨学科专业知识。在该奖项的K99阶段，布劳恩博士将利用教程、研讨会/会议和教学指导，在以下方面获得额外的培训：1)内分泌学概念和环境化学品对内分泌系统的影响；2)心理测试选择、管理、验证和解释；以及3)儿童神经发育。该培训将应用于一个最初的研究项目，在该项目中，布劳恩博士将在豪泽博士和贝林格博士的指导下，对豪泽博士的环境和生殖健康(地球)研究中的25名儿童进行视觉空间能力的计算机化测试。这些计算机化的测试类似于Morris水迷宫和放射臂迷宫，这两种迷宫用于动物神经毒性研究。使用这些新技能和环境(家庭)出生队列的预期健康结果和衡量标准，布劳恩博士将在该奖项的R00阶段解决两个具体目标：1)确定300名儿童孕期双酚A/邻苯二甲酸盐暴露是否与视觉空间能力有关，以及性别是否改变这些联系；2)确定330名婴儿孕期双酚A/邻苯二甲酸盐暴露是否与胎粪性类固醇浓度有关。布劳恩博士非常适合进行这项研究，因为他以前受过培训，而且他的导师、顾问和机构提供了独特的资源。这项拟议的培训和研究将使他能够研究内分泌细胞对其他荷尔蒙系统的影响，以及它们是否会增加儿童不良行为结果的风险。对性类固醇的检测将增进我们对EDC作用的潜在生物学机制的了解，使用动物类似物的神经行为测试将改善流行病学和动物研究之间的比较。公共卫生相关性：神经行为障碍给教育和医疗资源带来了巨大的负担；因此，首要任务是了解与这些障碍相关的因素。拟议的研究可以通过解决我们对双酚A和邻苯二甲酸盐神经毒性及其对人类神经行为的影响方面的重要研究空白，为公共卫生干预提供信息。 与公共卫生相关：胎儿可能容易受到内分泌干扰化合物的影响，如双酚A(BPA)和邻苯二甲酸盐。暴露在这些化合物中可能会扰乱妊娠性类固醇代谢，从而损害儿童的神经发育。该应用程序将使用内分泌干扰和儿童神经发育方面的综合培训计划，使Joe M.Braun博士做好准备，进行高质量的研究，研究妊娠期BPA/邻苯二甲酸盐暴露对胎儿性别、类固醇和儿童视觉空间能力的影响。

DESCRIPTION (provided by applicant) The fetal brain is uniquely sensitive and environmental chemical exposures and dysregulation of the endocrine system may increase the risk of adverse neurobehavioral outcomes like autism, attention-deficit/hyperactivity disorder, or depression. Under the mentorship of Drs. Bellinger and Hauser, this training and research plan will build upon Dr. Braun's expertise as an environmental epidemiologist and prepare him for a career studying endocrine disrupting compounds (EDCs) and their impact on hormonal systems and childhood neurodevelopment. Dr. Braun has never received formal training in these areas and few researchers possess this unique cross-disciplinary expertise. During the K99-phase of this award Dr. Braun will use tutorials, seminars/conferences, and didactic instruction to gain additional training in: 1) endocrinology concepts and the impact of environmental chemicals on the endocrine system; 2) psychometric test selection, administration, validation, and interpretation; and 3) childhood neurodevelopment. This training will be applied in an original research project where Dr. Braun will administer computerized tests of visuospatial ability to 25 children from Dr. Hauser's Environment and Reproductive Health (EARTH) study under the guidance of both Drs. Hauser and Bellinger. These computerized tests are analogues of the Morris Water Maze and Radial Arm Maze, which are used in animal studies of neurotoxicity. Using these new skills and the prospective Health Outcomes and Measures of the Environment (HOME) birth cohort, Dr. Braun will address two specific aims during the R00- phase of this award: 1) determine if gestational BPA/phthalate exposure is associated with visuospatial ability in 300 children and if sex modifies these associations and 2) determine if gestational BPA/phthalate exposure is associated with meconium sex steroid concentrations in 330 infants. Dr. Braun is well suited to carry out this research because of his prior training and the unique resources offered by his mentors, advisors, and institution. This proposed training and research will enable him to study the impact of EDCs on other hormonal systems and whether they increase the risk of adverse childhood behavioral outcomes. The examination of sex steroids will advance our knowledge of potential biological mechanisms of EDC action and the use of neurobehavioral tests with animal analogues will improve comparisons between epidemiological and animal studies. Public Health Relevance: Neurobehavioral disorders place an enormous burden on educational and medical resources; thus, priority is to understand factors associated with these disorders. The proposed studies could inform public health interventions by addressing important research gaps in our knowledge of BPA and phthalate neurotoxicity and its impact on human neurobehavior. Public Health Relevance: The fetus may be susceptible to endocrine disrupting compounds like bisphenol A (BPA) and phthalates. Exposure to these compounds may be detrimental to childhood neurodevelopment by disrupting gestational sex steroid metabolism. This application will use an integrated training plan in endocrine disruption and childhood neurodevelopment to prepare Dr. Joe M. Braun to produce high-quality research studying the impact of gestational BPA/phthalate exposures on fetal sex steroids and childhood visuospatial ability.