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.

项目概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动物模型显示暴露与不良结果之间的因果关系，人类流行病学数据支持 EDC 暴露与我的建议旨在研究围产期 EDC 暴露的影响。雌激素敏感神经中脑多巴胺（DA）回路的发育在这里，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 DAergic 行为缺陷调节细胞、分子和表观遗传过程的信号机制此外，妊娠期暴露会影响胎儿和发育中的大脑 DA 系统。胎儿性腺内发育的生殖细胞成为精子/卵子，导致 F2 因此，我的工作将集中于 F1 代和 F2 代的两性大鼠。为此，我将使用 Aroclor 1221 建立完善的多氯联苯 EDC 模型 (A1221)，一种弱雌激素混合物。妊娠期接触 A1221 会扰乱神经生物学。发育，并对神经内分泌功能、大脑基因表达有潜在影响，然而，它对注意力和情感奖励的影响。处理行为是未知的；这是暴露影响的一个重要知识空白。可以在两代中观察到：F1（在妊娠期间暴露）和 F2（在妊娠期间暴露）发育中的生殖细胞）。主要结果将是注意力和情感奖励的表现。处理成年期间的行为结果，因为这些行为对雌激素敏感并且与人类性别偏见的心理健康障碍有关。大脑多巴胺系统的神经解剖学组织发生相应变化，以及参与雌激素和多巴胺信号传导的基因的表达至少有一部分。脑组织的机制是通过激素对 DNA 甲基化的作用 “编程”这些基因在以后的生活中如何发挥作用，该研究还将确定表观遗传是否变化（DNA甲基化）是基因表达长期变化的机制在关键发育时期对 EDC 暴露的反应这些目标符合 NIEHS 的要求。 “研究环境对基因组结构和功能的影响”的战略目标，包括生物过程的表观遗传调控，同时将性作为一种生物学行为此外，该提案扩展了我们对环境影响的理解。与人类认知和行为障碍相关的行为和分子终点。