Transgenerational actions of the endocrine disrupting compound Bisphenol A

描述(申请人提供)：许多内分泌干扰化合物(EDCs)对暴露的个体有立竿见影的效果，但更复杂的问题是它们对后代的长期作用。来自人类的有限数据与动物的工作一致，表明暴露在内分泌细胞中，特别是在发育期间暴露，会导致疾病状态的微妙增加，以及跨代影响的证据。内分泌细胞对特定靶基因的确切表观遗传和/或遗传作用，在后续世代中产生稳定的修饰，目前尚不清楚。这个项目的第一个目标是了解由普遍存在的EDC，双酚A(BPA)的人类相关水平产生的跨代遗传的潜在机制。这项工作是首次测试与人类相关的双酚A暴露对大脑和行为的跨代行为。怀孕的近交系小鼠通过自愿摄入母体饮食而暴露于EDCs。在出生时，对照和双酚A幼崽被养育到控制饮食的水坝中，以隔离双酚A对怀孕的作用，并控制这些化合物对母体行为的任何后果。我们已经证明，在第一代和第四代(F4)小鼠中，BPA血统的一些社会行为与对照小鼠有显着不同。此外，F4双酚A暴露的小鼠大脑中调节社会行为的两个基因--加压素(AVP)和催产素(OXT)的mRNA量减少。实验一将确定双酚A作用传递的来源。此外，我们将评估这些小鼠的一些认知和情绪行为，以提高我们预测哪些人类疾病可能对BPA敏感的能力。在下一项研究中，将用下一代测序技术探测大脑区域，以建立目标基因。F3小鼠的大脑将被解剖成组成社会行为网络的核。将进行染色质免疫沉淀(CHIP-)和RNA测序的组合。这些数据为在大脑中发现的表观遗传修饰提供了靶点。所揭示的机制将适用于其他靶组织，从而适用于各种疾病。这项研究计划将为该领域提供双酚A跨代行为的模型和这些暴露的后果的表观基因组图。

DESCRIPTION (provided by applicant): Many endocrine disrupting compounds (EDCs) have immediate effects on exposed individuals, but more complex concerns surround their long term actions on subsequent generations. The limited data from humans concur with the animal work suggesting that exposure to EDCs, particularly exposure during development, produce subtle increases in disease states, along with evidence for transgenerational effects. The precise epigenetic and/or genetic actions of EDCs on specific target genes, which produce stable modifications in subsequent generations, are unknown. The first goal of this program is to understand the mechanisms underlying transgenerational inheritance produced by human-relevant levels of the ubiquitous EDC, Bisphenol A (BPA). The work proposed is the first to test transgenerational actions of human-relevant exposures of BPA on brain and behaviors. Pregnant inbred mice are exposed to EDCs via voluntary ingestion of maternal diet. At birth, control and BPA pups are fostered to dams on control diet to isolate the actions of BPA to gestation and control for any consequences of these compounds on maternal behavior. We have shown that several social behaviors in the first and fourth generation (F4) of mice the BPA lineage differ significantly from control mice. Moreover, mRNA for two genes that regulate social behavior, vasopressin (Avp) and oxytocin (Oxt), are decreased in brains of the F4 BPA-exposed mice. Experiment one will determine the parent of origin for transmission of BPA's actions. In addition we will assess a number of cognitive and emotional behaviors in these mice to improve our ability to predict which human diseases may be sensitive to BPA. In the next study brains regions are probed with next generation sequencing techniques to establish target genes. Brains from F3 mice will be dissected into the nuclei that compose the social behavior network. A combination of Chromatin Immunoprecipitation (ChiP-) and RNA-sequencing will be conducted. These data provide targets for the epigenetic modifications found in brain. The mechanisms revealed will be applicable to other target tissues and thus a variety of diseases. This research plan will provide the field with a model for transgenerational actions of BPA and an epigenomic map of the consequences of these exposures.