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

高度社会化加州小鼠模型中的内分泌干扰化学物质、表观遗传改变和自闭症样行为

• 批准号: 9338253
• 负责人: Cheryl Susan Rosenfeld
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338253
• 关键词: Adult; Affect; Affective; Amygdaloid structure; Animal Model; Animals; Anxiety; Autistic Disorder; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Brain; Brain region; California; Candidate Disease Gene; Categories; Chemicals; Child; Clinical; Cognitive; Cognitive deficits; DNA Methylation; Data; Deer Mouse; Development; Diagnosis; Diet; Disease; Dose; Endocrine Disruptors; Environmental Risk Factor; Epigenetic Process; Equipment; Estrogens; Ethinyl Estradiol; Etiology; Exhibits; Exposure to; Female; Gene Expression; Genes; Genetic; Genistein; Goals; Hand; Hippocampus (Brain); Human; Hypothalamic structure; Impairment; Incidence; Individual; Infant formula; International; Link; Measures; MicroRNAs; Mothers; Mus; Parents; Pathway Analysis; Pathway interactions; Patients; Pattern; Perinatal Exposure; Peromyscus; Phenotype; Phytoestrogens; Plants; Process; Reporting; Research; Risk; Rodent; Same-sex; Sex Behavior; Siblings; Societies; Statistical Data Interpretation; Study models; Testing; Transgenic Mice; Translating; anxiety-like behavior; autism spectrum disorder; base; bisphenol A; candidate marker; disorder risk; environmental chemical; experience; in utero; male; methylation pattern; mouse model; neurobehavioral; neurobehavioral disorder; novel; offspring; prenatal exposure; relating to nervous system; remediation; repetitive behavior; sex; social; social organization; soy; steroid hormone; trait; transcriptome; transcriptomics; treatment group; way finding; Adult; Affect; Affective; Amygdaloid structure; Animal Model; Animals; Anxiety; Autistic Disorder; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Brain; Brain region; California; Candidate Disease Gene; Categories; Chemicals; Child; Clinical; Cognitive; Cognitive deficits; DNA Methylation; Data; Deer Mouse; Development; Diagnosis; Diet; Disease; Dose; Endocrine Disruptors; Environmental Risk Factor; Epigenetic Process; Equipment; Estrogens; Ethinyl Estradiol; Etiology; Exhibits; Exposure to; Female; Gene Expression; Genes; Genetic; Genistein; Goals; Hand; Hippocampus (Brain); Human; Hypothalamic structure; Impairment; Incidence; Individual; Infant formula; International; Link; Measures; MicroRNAs; Mothers; Mus; Parents; Pathway Analysis; Pathway interactions; Patients; Pattern; Perinatal Exposure; Peromyscus; Phenotype; Phytoestrogens; Plants; Process; Reporting; Research; Risk; Rodent; Same-sex; Sex Behavior; Siblings; Societies; Statistical Data Interpretation; Study models; Testing; Transgenic Mice; Translating; anxiety-like behavior; autism spectrum disorder; base; bisphenol A; candidate marker; disorder risk; environmental chemical; experience; in utero; male; methylation pattern; mouse model; neurobehavioral; neurobehavioral disorder; novel; offspring; prenatal exposure; relating to nervous system; remediation; repetitive behavior; sex; social; social organization; soy; steroid hormone; trait; transcriptome; transcriptomics; treatment group; way finding

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.

项目摘要 越来越多的儿童被诊断出患有自闭症谱系障碍（ASD及其相关疾病 神经行为疾病。基于仅遗传学并未解释的发病率上升，它一直是 假设在子宫内接触环境化学物质可能会增加这些疾病的风险。 儿童通过母亲通过内分泌破坏化学物质（EDC）的围产期暴露，包括 双酚A（BPA）已与ASD链接。为了建立潜在的因果关系和潜在的机制， 在相关动物模型物种中测试这些化学物质很重要，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动物模型研究都采用了转基因小鼠。但是，这些动物通常无法 复制所有类似ASD的核心行为。一夫一妻制，二元和高度交流的加利福尼亚 小鼠（加州Peromyscus）为ASD研究提供了互补的动物模型。我们有 以前证明，加利福尼亚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及其女性兄弟姐妹 表现出更高的焦虑，让人联想到ASD儿童。男性和女性都在发展 接触BPA的成年人继续成为贫穷的父母。 我们将测试以下假设：早期暴露于BPA和Genastein（G），这是一种存在于 大豆产品（包括婴儿配方）会导致加利福尼亚小鼠类似ASD的行为障碍。这 第一个目标是确定早期暴露于BPA，G和两个EDC的组合是否会导致 在ASD患者中观察到的行为缺陷。第二个目标是确定男性和女性是否 暴露于这些化学物质显示基因表达/DNA甲基化/miRNA（miR）的变化 该地区（杏仁核，下丘脑和海马）的这些特征可能是破坏的基础 行为表型。 具体目的是：1）测试雄性和女性F1加利福尼亚小鼠的发育暴露于BPA， G和BPA + G会影响ASD儿童中断的行为领域，例如社会性 - 交流， 认知，焦虑/神经影响和重复行为。 2）测试这些人是否合并 EDC会影响F1雄性的杏仁核，海马和下丘脑的全球转录组谱。 可能支持EDC引起的行为中断的女性。 3）确定这些治疗方法是否 诱导杏仁核，海马和下丘脑的DNA甲基化和miR变化 并执行全面的相关分析以将各种生物分子和行为联系起来 干扰。数据可能会提供可用于诊断和潜在的新型候选生物标志物 由于早期暴露于这些EDC，儿童在ASD危险中的预防/补救策略。