Endocrine Disrupting Chemicals and Male-biased Neurobehavioral Disorders

内分泌干扰化学物质和男性神经行为障碍

基本信息

批准号：
10561338
负责人：
Marissa Sobolewski Terry
金额：
$ 37.58万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-03 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561338
关键词：
Adult Androgen Receptor Androgens Animals Attention Attention deficit hyperactivity disorder Basic Science Behavior Behavioral Behavioral Assay Binding Biological Birth Brain Central Nervous System Chemical Actions Chemical Exposure Child Corpus striatum structure Cytosine DNA DNA Methylation DNA Modification Methylases Data Development Disease Dose Economics Embryo Endocrine Endocrine Disruptors Epidemiology Epigenetic Process Estrogen Receptor alpha Etiology Event Exposure to Female Financial cost Future Genes Genetic Models Genome Health protection Heterogeneity Human Impulsivity Incidence Individual Infant Investigation Knowledge Link Longevity Measurable Measures Mediating Methyltransferase Molecular Mouse Strains Mus Neonatal Neurodevelopmental Disorder Neurons Newborn Infant Pathway interactions Pattern Perinatal Phenocopy Phenotype Polychlorinated Biphenyls Public Health Reporting Research Research Personnel Risk Risk Assessment Rodent Role Sampling Sentinel Series Serum Sex Differences Sex Differentiation Signal Transduction Social Behavior System Targeted Research Techniques Testing Testosterone Toxic effect Translating Ventral Striatum autism spectrum disorder bisphenol A cell type cellular targeting demethylation early childhood early onset embryonic stem cell experience experimental study genome-wide genotypic sex hypothalamic pituitary gonadal axis imprint life time cost male nerve stem cell nervous system development neural neurobehavioral disorder neurotoxicity perfluorooctanoic acid preference repetitive behavior sex social social communication social deficits

项目摘要

Children’s neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASDs), have tremendous societal, economic, and personal consequences. The incidence rates and behavioral presentation of these disorders vary by genetic sex, with a male bias. While multifactorial risks have been reported for this male bias, the mechanistic origins remain unresolved. Increasingly, epidemiological and animal studies identify a role for endocrine disrupting chemical (EDCs) exposures in the etiology of children’s NDDs. However, translating risk is difficult because early childhood exposures are increasingly characterized by low dose exposures to mixtures of EDCs, as exemplified by a recent study that found 90% of newborn children had measurable serum levels of both bisphenol-a (BPA) and perfluorooctanoic acid (PFOA) at birth. Our previous data utilizing a curated mixture (MIX) of EDCs, representative of these infant exposures, found that a low dose EDC mixture altered testosterone (T) levels in male mice at birth and resulted in male-specific behavioral changes, including reduced attention, impulsivity, and reduced sociability, phenotypes seen in ADHD and ASDs. Occurring in both rodents and humans, males experience a surge of T shortly before and after birth that is essential for nervous system development. Our data indicate that T at birth may be a sensitive target of multiple EDC mixtures. MIX exposure also marginally reduced DNA methyltransferase (DNMT1) levels and hypomethylated sensitive imprinted genes in male striatum, a region essential for these behavioral domains. DNA methylation profiles are influenced by various EDCs and suggested as a potential mechanism by which EDCs confer risk. Consequently, this proposal will investigate a hypothesized mechanistic pathway linking EDC-induced elevated T levels at birth with DNA hypomethylation in striatum as a mechanism of sex-dependent behavioral deficits. This hypothesis will be examined in a series of 3 Aims that systematically manipulate endocrine and epigenetic signals and track brain and behavioral function into adulthood. First, it will test the ability of neonatal T administration to phenocopy both the epigenetic and behavioral consequences of MIX EDC exposure. In addition, the role of EDC-induced DNA hypomethylation via DNMT inhibition will be tested using a genetically modified strain of mice with reduced DNMT1 activity. Because epigenetic mechanisms of brain development are highly region and cell-type specific, and our prior assessments used whole striatum, the proposed aims will investigate genome-wide DNA methylation profiles in neurons from ventral striatum. As an essential step forward, this proposal will integrate translational behavioral assays and advanced epigenetic techniques to inform our understanding of male vulnerability. The perinatal T surge is an understudied target of EDC neurotoxicity. The proposed studies will significantly expand our limited knowledge of how EDC mixtures alter CNS development in a sex-dependent fashion and will provide new data that are essential for risk assessment and public health protection.

儿童神经发育障碍（NDDS），例如注意力缺陷/多动症（ADHD）和自闭症谱系障碍（ASD）具有巨大的社会，经济和个人后果。这些疾病的发病率和行为表现因遗传性别而异，男性偏见。尽管已经报道了这种男性偏见的多因素风险，机械起源仍未解决。流行病学和动物研究越来越多地确定了内分泌干扰化学（EDC）的作用儿童NDD病因的暴露。但是，转化风险很困难，因为幼儿期暴露越来越多地以低剂量暴露于EDC的混合物中，例如最近的研究发现，有90％的新生儿童具有可测量的血清Bisphenol-A（BPA）和出生时全氟辛酸（PFOA）。我们以前利用EDC的策划混合物（混合）的数据，代表这些婴儿暴露，发现低剂量EDC混合物改变了睾丸激素（T）雄性小鼠出生时，导致男性特异性行为变化，包括降低注意力，冲动性，以及降低社交能力，在ADHD和ASD中看到的表型。发生在啮齿动物和人类中，男性出生前后不久的T激增对于神经系统发展至关重要。我们的数据表明T时T可能是多种EDC混合物的敏感靶标。混合曝光也很小 DNA甲基转移酶（DNMT1）的降低和雄性敏感印记基因的水平降低纹状体，这些行为领域必不可少的区域。 DNA甲基化谱受各种影响 EDC并建议作为EDCS会议风险的潜在机制。因此，该提议将研究一种假设的机械途径，该途径连接了EDC诱导的DNA出生时T水平的升高纹状体中的低甲基化是性别依赖性行为缺陷的机制。这个假设将是在一系列3个目标中进行了检查，该目标可以系统地操纵内分泌和表观遗传信号并跟踪大脑和行为功能成年。首先，它将测试新生T给药的能力混合EDC暴露的表观遗传和行为后果。另外，EDC诱导的作用 DNA通过DNMT抑制作用的DNA低甲基化将使用一定经过修饰的小鼠菌株进行测试 DNMT1活性降低。因为大脑发育的表观遗传机制是高度区域和细胞类型具体，我们先前的评估使用了整个纹状体，拟议的目标将研究全基因组DNA 来自腹侧纹状体的神经元中的甲基化谱。作为重要的一步，该提议将整合翻译行为分析和高级表观遗传技术，以告知我们对男性的理解脆弱性。围产期T激增是EDC神经毒性的一个理解靶标。拟议的研究将大大扩展了我们对EDC混合物如何改变性别依赖性中枢神经系统发展的有限了解时尚，将提供新数据，这些数据对于风险评估和公共卫生保护至关重要。