Endocrine Disrupting Chemicals, Epigenetic Alterations, and Autism-Like Behaviors in the Highly Social California Mouse Model

项目摘要 越来越多的儿童被诊断患有自闭症谱系障碍（ASD及相关疾病）。 神经行为障碍基于发病率的上升并不能仅仅用遗传学来解释， 假设子宫内暴露于环境化学物质可能会增加这些疾病的风险。 围产期儿童通过母亲接触内分泌干扰化学品，包括 双酚A（BPA）与ASD有关。为了确定潜在的因果关系和潜在的机制， 重要的是在相关动物模型物种中测试这些化学品，其中临床核心 ASD儿童表现出的行为症状可以复制。 迄今为止，大多数ASD动物模型研究采用转基因小鼠。然而，这些动物往往未能 复制所有的核心类自闭症行为。一夫一妻制，双亲，和高度沟通的加州 小鼠（Peromyscuscalifornicus）为ASD研究提供了补充的动物模型。我们有 先前的研究表明，加州小鼠的神经行为编程特别容易受到BPA的影响。 发育中暴露的男性表现出受损的社会性行为，他们的女性兄弟姐妹 表现出高度的焦虑让人想起自闭症儿童无论是男性还是女性， 暴露在BPA中的孩子长大后会成为贫穷的父母。 我们将检验早期暴露于BPA和染料木黄酮（G）的假设，染料木黄酮是一种植物雌激素， 大豆制品--包括婴儿配方奶粉--导致加州小鼠出现类似ASD的行为障碍。的 第一个目标是确定早期接触BPA、G以及两种内分泌干扰物的组合是否会导致 ASD患者中观察到行为缺陷。第二个目标将是确定男性和女性是否 暴露于这些化学物质的人显示大脑亚细胞中的基因表达/DNA甲基化/miRNA（miR）变化， 控制这些特征的区域（杏仁核、下丘脑和海马体）可能是破坏这些特征的基础。 行为表型 具体目的是：1）测试雄性和雌性F1加州小鼠发育暴露于BPA， G和BPA + G影响ASD儿童的行为领域，如社交-性-沟通， 认知、焦虑/神经情感和重复行为。2)测试这些个体和组合 内分泌干扰物影响F1雄性大鼠杏仁核、海马和下丘脑的整体转录组学特征， 女性可能会导致内分泌干扰综合症引起的行为中断。3)确定这些治疗是否 在两种F1性别中诱导杏仁核、海马和下丘脑中的DNA甲基化和miR变化 并进行全面的相关性分析，将各种生物分子和行为 干扰.数据可能会提供新的候选生物标志物，可用于诊断和潜在的 预防/补救策略的儿童在ASD的风险，由于早期暴露于这些内分泌干扰物。

Project Summary Increasing numbers of children are being diagnosed with autism spectrum disorders (ASD and related neurobehavioral disorders. Based on the rising incidence that is not explained by genetics alone, it has been postulated that in utero exposure to environmental chemicals may increase the risk for these disorders. Perinatal exposure of children through the mother to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), has been linked to ASD. To establish potential causation and underlying mechanisms, it is important to test these chemicals in a relevant animal model species, where the clinical core behavioral symptoms exhibited by ASD children can be replicated. Most ASD animal model studies to date have employed transgenic mice. However, these animals often fail to replicate all of the core ASD-like behaviors. The monogamous, biparental, and highly communicative California mouse (Peromyscus californicus) provides a complementary animal model for ASD research. We have previously demonstrated that neurobehavioral programming in California mice is especially vulnerable to BPA. Developmentally exposed males demonstrate compromised socio-sexual behaviors, and their female siblings exhibit heightened anxiety, reminiscent of children with ASD. Both males and females developmentally exposed to BPA go on to become poor parents as adults. We will test the hypothesis that early exposure to BPA and genistein (G), a phytoestrogen present in soy products- including baby formulas, results in ASD-like behavioral disorders in California mice. The first goal will be to ascertain whether early exposure to BPA, G, and the combination of the two EDCs results in behavioral deficits observed in ASD patients. The second goal will be to determine whether males and females exposed to these chemicals show gene expression/DNA methylation/miRNA (miR) changes in the brain sub- regions (amygdala, hypothalamus and hippocampus) governing these traits that may underlie the disrupted behavioral phenotypes. Specific Aims are to: 1) Test whether developmental exposure of male and female F1 California mice to BPA, G, and BPA + G affects behavioral domains disrupted in ASD children, such as social-sexual-communicative, cognitive, anxiety/neuro-affective, and repetitive behaviors. 2) Test whether these individual and combined EDCs affect global transcriptomic profiles in the amygdala, hippocampus and hypothalamus in F1 males and females that may underpin the EDC-induced behavioral disruptions. 3) Determine whether these treatments induce DNA methylation and miR changes in the amygdala, hippocampus and hypothalamus in both F1 sexes and perform a comprehensive correlation analysis to link the various bio-molecular and behavioral disturbances. Data will likely provide novel candidate biomarkers that can be used to diagnose and in potential preventative/remediation strategies in children at-risk for ASD due to early exposure to these EDCs.