Prenatal Bisphenol A and Sexually Dimorphic Neurodevelopment

描述（由申请人提供）：几乎所有美国居民的组织中都含有可检测水平的双酚A（BPA）。它的雌激素特性已经被认识了几十年。虽然BPA过去被认为是弱雌激素，但现在很可能暴露于低剂量的BPA会对雄激素和雌激素反应组织产生破坏性影响。在BPA暴露的潜在健康后果中，干扰大脑发育的正常过程被认为是最令人担忧的。这些担忧的出现是因为发育中的神经系统是BPA的关键目标;性腺激素水平塑造了围产期发育期间的大脑组织，特别是性别分化。异常的大脑发育是异常行为功能的基础，其影响延伸到整个生命周期，甚至进入神经退行性疾病的领域。尽管关于早期发育暴露于BPA的神经行为后果的报道越来越多，但文献仍然不完整，而且有些不一致。原因包括：数据太有限，无法表征剂量-反应关系，倾向于关注孤立的结果，以及令人遗憾的是，缺乏关于人类的明确信息。这项建议在几个方面克服了这些限制。(1)它尽可能地协调人类和动物的行为指数。(2)它测量两种物种的暴露生物标志物（尿液、血液或两者）。(3)它包括几个行为终点，包括认知功能。(4)它提供了机械的措施。(5)它包括从低到高的暴露水平范围。该项目包括三个组成部分。在人类部分，将再次联系一组儿童，这些儿童的母亲参加了2000-2005年的一项大型前瞻性研究，并提供了怀孕中期的血液和尿液样本。先前在这些样本的一个子集中测量了尿邻苯二甲酸酯代谢物，发现与男性生殖器发育有显著相关性。这些儿童中的一部分在4-7岁时再次接触，并检查了产前邻苯二甲酸酯暴露与母亲报告的游戏行为的关系，发现了显著的关联（在本申请中描述）。这些儿童现在5-9岁，母亲将被要求提供有关其儿童的认知技能、性相关游戏行为、社会行为和身体活动的信息。这些将使用储存的尿液和血液样本进行检查，与共轭和非共轭BPA以及邻苯二甲酸酯代谢物（如可用）有关。在动物行为部分，我们将使大鼠在围产期暴露于BPA和阳性对照（DES），并测量认知功能、游戏行为和活动模式。将在啮齿动物血清中测定结合和非结合BPA。在机械组成部分，大脑结构和功能，特别是有关性别二型指数将进行评估。为此，围产期暴露于BPA将与两个性二态脑区的体积有关，前腹侧室周核（AVPV）和视前区性二态核（SDN-POA）和相关的神经标记物。这项拟议中的研究解决了一个被公众和科学审查小组视为衡量环境暴露于BPA所带来风险的关键问题。也就是说，它对大脑发育的影响是什么，这些影响是性别特异性的吗？通过关注被认为是两性异形的终点，以及在早期发育过程中大脑性别分化产生的终点，一个协调的信息基础将随之而来，这将以一种迄今为止不可能的更明确的方式对该问题和相关问题产生答案。所产生的数据将是新颖的，不仅可能表明一个新的和重要的端点BPA毒性的基础上环境相关的水平，但应该促进一个领域，这是相当新的环境健康科学：使用性别特异性神经发育终点，以确定内分泌干扰。证明目前使用的（和新的）环境化学品对男性和女性发育终点的不同影响可能成为该化学品产生内分泌干扰能力的标志。此外，早期发育之后的随访研究可能会在以后的生活中显示出持续的影响，包括潜在的异常社会行为，学习和学校表现受损，母亲和儿童养育行为受损，以及以后神经退行性疾病的风险增加。这些问题并不局限于科学界的讨论。公众是积极的参与者。孕妇尤其担心让婴儿接触可能改变大脑发育的化学物质。该项目旨在获得全面、协调的信息，为负责保护公众健康的管理当局和关心子女未来健康的妇女提供决策依据。 公共卫生相关性：该项目将提供关于出生前暴露于双酚A（BPA）如何改变产前发育期间大脑男性化和女性化的独特信息。随后的研究，超越婴儿期和儿童期，可能会在以后的生活中显示出持续的影响，包括潜在的异常社会行为，学习和学校表现受损，母亲和儿童养育行为受损，以及以后神经退行性疾病的风险增加。

DESCRIPTION (provided by applicant): Virtually all US inhabitants carry detectable levels of bisphenol-A (BPA) in their tissues. Its estrogenic properties have been recognized for decades. Although BPA had been viewed as weakly estrogenic in the past, it is now likely that exposure to low doses of BPA can produce disruptive effects in androgen and estrogen responsive tissues. Among the potential health consequences of BPA exposure of concern, interference with the normal processes of brain development is viewed as one of the most worrisome. These concerns arise because the developing nervous system is a key target of BPA; gonadal hormone levels mold brain organization, particularly sexual differentiation, during perinatal development. Aberrant brain development is the basis of aberrant behavioral function, whose effects extend across the entire lifespan, even into the realm of neurodegenerative disease. Despite the growing volume of reports on the neurobehavioral consequences of early developmental exposure to BPA, the literature remains fragmentary and somewhat inconsistent. Among the reasons are: data too limited to allow for characterization of dose-response relationships, the tendency to focus on isolated outcome(s), and, glaringly, the absence of definitive information on humans. This proposal confronts these limitations in several ways. (1) It coordinates, to the degree possible, human and animal behavioral indices. (2) It measures exposure biomarkers in both species (in urine, blood, or both). (3) It encompasses several behavioral endpoints, including cognitive function. (4) It provides mechanistic measures. (5) It includes a range of exposure levels from low to high. The project contains three components. In the human component a cohort of children whose mothers were enrolled in a large prospective study in 2000-2005 and provided samples of blood and urine during mid-pregnancy will be contacted again. Previously urinary phthalate metabolites were measured in a subset of these samples and significant associations were discovered with male genital development. A subset of these children were then recontacted at 4-7 years and examined for prenatal phthalate exposure in relation to mother's reports of play behavior, and significant associations (described in this application) were found. The children are now 5-9 years old and mothers will be asked to provide information on their children's cognitive skills, sex-linked play behaviors, social behaviors, and physical activity. These will be examined using stored urine and blood samples, in relation to conjugated and unconjugated BPA, as well as phthalate metabolites when available. In the animal behavior component we will expose rats will be exposed perinatally to BPA and a positive control (DES) and to measure aspects of cognitive function, play behavior, and activity patterns. Conjugated and unconjugated BPA will be determined in rodent serum. In the mechanistic component brain structures and functions especially relevant to sexually dimorphic indices will be assessed. To this end, perinatal exposure to BPA will be related to the volume of two sexually dimorphic brain regions, the anterior ventral periventricular nucleus (AVPV) and the sexually dimorphic nucleus of the preoptic area (SDN-POA) and associated neural markers. The proposed research addresses a question seen by both the public and by scientific review panels as crucial to weighing the risks posed by environmental exposure to BPA. Namely, what are its effects on brain development, and are these gender-specific? By focusing on endpoints recognized as sexually dimorphic, and which arise from sexual differentiation of the brain during early development, a coordinated base of information will ensue that should yield answers to that and related questions in a more definitive manner than has not been possible until now. Data produced will be novel and may not only indicate a new and important endpoint for BPA toxicity based on environmentally relevant levels, but should promote a field that is rather new to environmental health science: use of gender-specific neurodevelopmental endpoints to identify endocrine disruption. Demonstration of differing effects for a currently used (and novel) environmental chemical on male and female developmental endpoints may become a flag for the ability of that chemical to produce endocrine disruption. Moreover, follow-up studies beyond early development may show persistent effects later in life, including potentially aberrant social behaviors, impaired learning and school performance, impaired maternal and child-rearing behaviors and, later, enhanced risks of neurodegenerative disease. These issues are not confined to discussions within the scientific community. The public is an active participant. Pregnant women are especially anxious about exposing their babies to chemicals that may alter brain development. The comprehensive, coordinated body of information this project is designed to procure will provide the basis for decisions by regulatory authorities charged with protecting public health and by women concerned about the future health of their children. PUBLIC HEALTH RELEVANCE: This project will provide unique information on how exposure to bisphenol A (BPA) before birth can alter masculinization and feminization of the brain during prenatal development. Subsequent studies, beyond infancy and childhood, may show persistent effects later in life as well, including potentially aberrant social behaviors, impaired learning and school performance, impaired maternal and child-rearing behaviors and, later, enhanced risks of neurodegenerative disease.