Endocrine Disruption of the Developing Dopamine System

发育中的多巴胺系统的内分泌干扰

基本信息

批准号：
10601273
负责人：
Emily Nicole Hilz
金额：
$ 6.91万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601273
关键词：
Address Adult Affect Affective Animal Model Attention Attention deficit hyperactivity disorder Behavior Behavior Disorders Behavioral Biological Biological Process Brain Chemical Actions Chemical Exposure Chemical Models Cognition Disorders Cognitive Cognitive deficits Corpus striatum structure DNA DNA Methylation Development Developmental Process Disease Dopamine Dopamine Receptor Embryonic Development Endocrine Endocrine Disruptors Endocrine disruption Environment Epigenetic Process Estradiol Estrogen Receptors Estrogens Exposure to Female Fetus Future Gene Expression Generations Genes Genome Germ Cells Goals Gonadal structure Health Health Policy Hormones Human Immunohistochemistry Impaired cognition Impairment In Situ Hybridization Individual Intervention Knowledge Learning Life Life Cycle Stages Link Mediating Medical Mental disorders Mentorship Midbrain structure Modeling Molecular Moods Mus National Institute of Environmental Health Sciences Neuroanatomy Neurobiology Neurons Neurosecretory Systems Organism Outcome Ovum Pathway interactions Perinatal Perinatal Exposure Phenotype Polychlorinated Biphenyls Prefrontal Cortex Pregnancy Process Proteins Public Health RNA Rattus Receptor Gene Reproductive Behavior Research Rewards Sex Bias Signal Transduction Social Behavior Structure System Techniques Testing Time Training Work adverse outcome behavior test behavioral outcome behavioral phenotyping bisulfite sequencing brain tissue career development critical developmental period dopamine system dopamine transporter epidemiologic data epigenetic regulation estrogen disruption estrogenic experience exposed human population fetal gene function hormonal signals intergenerational male methylation pattern neural neurobehavioral neurobehavioral disorder neurodevelopment nonhuman primate offspring preference primary outcome programs protein expression response reward processing sex sperm cell training opportunity

项目摘要

PROJECT SUMMARY Endocrine-disrupting chemicals (EDCs) affect a wide range of endocrine and neurobiological functions. Animal models show causal relationships between exposure and adverse outcomes, and epidemiological data in humans support correlations between EDC exposure and neurobehavioral deficits. My proposal seeks to investigate the effects of perinatal EDC exposure on the development of estrogen-sensitive neural midbrain dopamine (DA) circuits involved in attentional and affective reward-processing behaviors. Here, I will test the hypothesis that perinatal EDC exposure will lead to deficits in DAergic behaviors via disruption of estrogenic signaling mechanisms that regulate cellular, molecular and epigenetic processes in the developing brain DA system. Furthermore, gestational exposure affects both the fetus and developing germ cells within the fetal gonad that become the sperm/ova leading to the F2 generation. Therefore, my work will focus on rats of both sexes in the F1 and F2 generations. To do this, I will utilize a well-established EDC model of polychlorinated biphenyls using Aroclor 1221 (A1221), a weakly estrogenic mixture. Gestational exposure to A1221 perturbs neurobiological development, and has latent effects on neuroendocrine functions, gene expression in the brain, and behavior, in a sex-specific manner. However, its influence on attentional and affective reward- processing behaviors is unknown; this is an important gap in knowledge. Effects of exposures will be observed across two generations: F1 (exposed during gestation) and F2 (exposed as developing germ cells). A primary outcome will be the display of attentional and affective reward- processing behavioral outcomes during adulthood, as these behaviors are estrogen-sensitive and associated with sex-biased mental health disorders in humans. Additionally, I will quantify corresponding changes in the neuroanatomical organization of the brain’s dopamine system, and expression of genes involved in estrogen and dopamine signaling. Because at least part of the mechanism for brain organization is through actions of hormones on DNA methylation to “program” how these genes function later in life, the research will also determine if epigenetic changes (DNA methylation) are a mechanism for long-term changes in gene expression in response to EDC exposure during critical developmental periods. These goals meet the NIEHS’ strategic goal to “investigate the effects of the environment on genome structure and function”, including epigenetic regulation of biological processes, while including sex as a biological variable. Moreover, the proposal extends our understanding of environmental influences on behavioral and molecular endpoints relevant to cognitive and behavioral disorders in humans.

项目摘要内分泌干扰化学物质（EDC）影响广泛的内分泌和神经生物学功能。动物模型显示暴露与不利结果之间的因果关系，人类的流行病学数据支持EDC暴露与神经行为缺陷。我的建议旨在调查围产期EDC暴露的影响关于雌激素敏感的神经中脑多巴胺（DA）电路的发展注意力和情感奖励处理行为。在这里，我将检验以下假设围产期EDC暴露将通过破坏雌激素而导致DAERCIC行为定义调节细胞，分子和表观遗传过程的信号传导机制开发大脑DA系统。此外，妊娠暴露会影响胎儿和在胎儿性腺内开发生殖细胞，这成为精子/OVA，导致F2 一代。因此，我的工作将集中在F1和F2世代中男女的大鼠上。到这样做，我将使用Aroclor 1221使用良好的多氯联苯的EDC模型（A1221），一种弱雌激素混合物。妊娠暴露于A1221的神经生物学发育，对神经内分泌功能，大脑中的基因表达具有潜在影响，和行为，以性别为特定的方式。但是，它对注意力和情感奖励的影响 - 处理行为未知；这是知识的重要差距。暴露的影响将可以观察到两代人：F1（妊娠期间暴露）和F2（暴露为发育生殖细胞）。主要结果将是展示注意力和情感奖励 - 在成年期处理行为结果，因为这些行为对雌激素敏感，并且与人类的性偏见心理健康障碍有关。另外，我将量化大脑多巴胺系统神经解剖组织的相应变化，以及参与雌激素和多巴胺信号传导的基因的表达。因为至少一部分大脑组织的机制是通过激素对DNA甲基化的作用 “程序”这些基因在以后的生活中如何发挥作用，研究还将确定是否表观遗传变化（DNA甲基化）是基因表达长期变化的机制在关键发育期间对EDC暴露的反应。这些目标符合Niehs “研究环境对基因组结构和功能的影响”的战略目标，包括对生物过程的表观遗传调节，而包括性别为生物学多变的。此外，该提案扩展了我们对环境影响的理解与人类的认知和行为障碍有关的行为和分子终点。