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

基本信息

批准号：
10016304
负责人：
R. MICHAEL ROBERTS
金额：
$ 37.82万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-08-31
项目状态：
已结题

项目摘要

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.

项目概要越来越多的儿童被诊断患有自闭症谱系障碍（ASD 和相关疾病）神经行为障碍。基于发病率的上升不能仅用遗传学来解释，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。儿童在围产期通过母亲接触内分泌干扰化学物质 (EDC)，包括双酚 A (BPA) 与自闭症谱系障碍 (ASD) 有关。为了建立潜在的因果关系和根本机制，在相关动物模型物种中测试这些化学物质非常重要，其中临床核心自闭症儿童表现出的行为症状是可以复制的。迄今为止，大多数 ASD 动物模型研究都采用转基因小鼠。然而，这些动物常常无法复制所有类似 ASD 的核心行为。一夫一妻制、双亲且善于沟通的加州小鼠（Peromyscus californicus）为 ASD 研究提供了补充动物模型。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，而他们的女性兄弟姐妹表现出高度的焦虑，让人想起患有自闭症谱系障碍的儿童。无论是男性还是女性都在发育接触 BPA 后，成年后会成为贫穷的父母。我们将检验以下假设：早期接触 BPA 和染料木黄酮 (G)（一种存在于体内的植物雌激素）豆制品（包括婴儿配方奶粉）会导致加州小鼠出现类似自闭症谱系障碍的行为障碍。这第一个目标是确定早期接触 BPA、G 以及两种 EDC 的组合是否会导致自闭症谱系障碍 (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中，大脑亚组中的基因表达/DNA甲基化/miRNA (miR)发生变化控制这些特征的区域（杏仁核、下丘脑和海马体）可能是破坏性的基础行为表型。具体目标是： 1) 测试雄性和雌性 F1 California 小鼠的发育是否暴露于 BPA， G 和 BPA + G 会影响 ASD 儿童的行为领域，例如社交、性、交流、认知、焦虑/神经情感和重复行为。 2）测试这些单独和组合是否 EDC 影响 F1 雄性和女性可能会导致 EDC 引起的行为障碍。 3）确定是否进行这些处理诱导 F1 性别中杏仁核、海马和下丘脑的 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联系起来干扰。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针对因早期接触这些 EDC 而面临自闭症谱系障碍 (ASD) 风险的儿童的预防/补救策略。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-Term Effects of Developmental Exposure to Oxycodone on Gut Microbiota and Relationship to Adult Behaviors and Metabolism.

发育期接触羟考酮对肠道微生物群的长期影响以及与成人行为和代谢的关系。

DOI：
发表时间：
2022-08-30
期刊：
影响因子：
6.4
作者：
Lyu, Zhen;Schmidt, Robert R;Martin, Rachel E;Green, Madison T;Kinkade, Jessica A;Mao, Jiude;Bivens, Nathan J;Joshi, Trupti;Rosenfeld, Cheryl S
通讯作者：
Rosenfeld, Cheryl S

miRNA changes in the mouse placenta due to bisphenol A exposure.

由于双酚 A 暴露，小鼠胎盘中的 miRNA 发生变化。