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 (NDD)，例如注意力缺陷/多动障碍 (ADHD) 和自闭症谱系障碍 (ASD) 会产生巨大的社会、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，但以男性为主。据报道，这种男性偏见存在多因素风险，但其机制根源仍未解决。流行病学和动物研究越来越多地确定内分泌干扰化学物质 (EDC) 的作用然而，由于幼儿期，翻译风险很困难。暴露越来越多地表现为低剂量暴露于 EDC 混合物，例如最近的一项研究发现，90% 的新生儿血清中双酚 A (BPA) 和我们之前的数据使用了 EDC 的混合物 (MIX)，这些婴儿暴露的代表，发现低剂量的 EDC 混合物改变了婴儿体内的睾酮 (T) 水平雄性小鼠在出生时受到影响，并导致雄性特有的行为变化，包括注意力下降、冲动、社交能力下降，这种现象在啮齿动物和人类（男性）中都存在。在出生前后不久会经历 T 的激增，这对于神经系统的发育至关重要。数据表明，出生时的 T 可能是多种 EDC 混合物暴露的敏感目标。男性 DNA 甲基转移酶 (DNMT1) 水平降低和低甲基化敏感印记基因纹状体是这些行为域所必需的区域，受到各种因素的影响。 EDC 并建议作为 EDC 赋予风险的潜在机制，该提案将进行测试。研究将 EDC 诱导的出生时 T 水平升高与 DNA 联系起来的机制途径纹状体的低甲基化是性别依赖性行为缺陷的机制。通过一系列 3 个目标进行检查，系统地操纵内分泌和表观遗传信号并跟踪大脑首先，它将测试新生儿 T 给药进行表型复制的能力。 MIX EDC 暴露的表观遗传和行为后果此外，EDC 诱导的作用。将使用具有 DNMT 抑制作用的转基因小鼠品系来测试 DNA 低甲基化因为大脑发育的表观遗传机制是高度区域和细胞类型的。具体而言，我们之前的评估使用了整个纹状体，拟议的目标将调查全基因组 DNA 作为向前迈出的重要一步，该提案将整合腹侧纹状体神经元的甲基化谱。转化行为测定和先进的表观遗传学技术可以帮助我们了解男性围产期 T 激增是 EDC 神经毒性的一个未充分研究的目标。显着扩展了我们对 EDC 混合物如何改变性别依赖性中枢神经系统发育的有限知识时尚并将提供对风险评估和公共卫生保护至关重要的新数据。