Project 2: Exposomics of Endocrine Disruption

项目2：内分泌干扰的暴露组学

• 批准号: 9919583
• 负责人: MARTYN T SMITH
• 金额: $ 27.45万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9919583
• 关键词: Address; Adipocytes; Adrenal Cortex Hormones; Adverse effects; Agonist; Androgen Receptor; Androgens; Animal Model; Aromatase; Aromatic Polycyclic Hydrocarbons; Arsenic; Benzene; Benzo(a)pyrene; Binding; Biological; Biological Assay; Biological Markers; Blood Cells; Cell Line; Cell model; Cells; Chemicals; Chronic; Data; Dexamethasone; Dose; Endocrine; Endocrine disruption; Endocrine system; Environment; Environmental Risk Factor; Epithelial Cells; Estrogen Receptors; Estrogens; Exposure to; Formaldehyde; Functional disorder; Genes; Glucocorticoid Receptor; Glucocorticoids; Glucose; Goals; Gonadal Steroid Hormones; Health; Hepatocyte; Hormones; Human; Hydrocortisone; In Vitro; Life; Lipids; Liver; Lung; Mammalian Cell; Mass Spectrum Analysis; Measures; Metabolic; Modeling; Mus; Obesity; Pathway interactions; Physiological; Plasma; Poison; Policies; Population; Production; Psychosocial Stress; Publishing; Receptor Signaling; Response Elements; Risk; Risk Assessment; Signal Recognition Particle; Signal Transduction; Spleen; Steroid biosynthesis; Steroids; Stress; Superfund; Tissues; Trichloroethylene; androgenic; base; biological adaptation to stress; carcinogenesis; carcinogenicity; cell type; design; environmental chemical; environmental stressor; epidemiology study; estrogen disruption; estrogenic; estrogenic activity; exposed human population; glucocorticoid receptor alpha; human subject; in vitro Assay; in vivo; leydig interstitial cell; male; metabolomics; monomethylarsonic acid; muscle form; neurobehavioral; non-genetic; novel; novel strategies; receptor; receptor expression; recruit; reproductive; response; screening; social factors; steroid hormone; superfund chemical; tissue biomarkers; transcriptome

PROJECT 2: SUMMARY/ABSTRACT Arsenic, benzene, trichloroethene (TCE), formaldehyde, and polycyclic aromatic hydrocarbons (PAHs) may have endocrine-disrupting effects at lower doses than those required for hematotoxicity or cancer induction. There is some evidence that they can modulate steroid hormone levels in both the corticosteroid and sex steroid pathways, potentially causing multiple adverse health effects. Here we propose to examine the disrupting effects of these common Superfund contaminants on glucocorticoid and sex steroid hormones and their tissue-specific effects in cell lines in vitro, mice in vivo, and perhaps most importantly in humans with well- characterized exposures. Endogenous cortisol is produced in response to stress and acts on the glucocorticoid receptor (GR) triggering metabolic and other disruptions. Environmental chemicals can also impact the GR pathway and are defined as “stressogens.” An example is arsenic, which alters GR signaling, but the mechanisms by which this impacts different cell types expressing GR are unclear. Cumulative risk assessment of non-genetic environmental stressors is a priority of EPA and we have developed novel approaches to do so under the exposome paradigm. Our first central hypothesis is that arsenic is a stressogen that alters GR activity, alone and in conjunction with other chemicals, with tissue-specific biological consequences. We propose to use an exposomic approach to understand the dose-dependent effects of arsenic, alone and in conjunction with other Superfund contaminants, on the glucocorticoid pathway in liver, adipocyte and blood cells in vitro; in mice in vivo; and in exposed humans (Aims 1-3). We will use a sensitive GR activity bioassay to screen Superfund contaminants that alter GR activity and will measure total glucocorticogenic (G) activity in media from exposed cells and in small volumes of human plasma from subjects exposed to arsenic. Use of the GR bioassay directly with plasma is novel. Our preliminary screening data show that arsenic is a GR antagonist and the PAH benzo(a)pyrene, an agonist. Arsenic, as well as TCE, benzene, formaldehyde and PAHs also cause adverse reproductive effects potentially by modulating natural estrogen and androgen sex hormones. Thus, our second central hypothesis is that these contaminants modulate estrogen receptor (ER) and androgen receptor (AR) activity by altering natural sex hormone levels. We will screen chemical effects on the production of these hormones (steroidogenesis) in validated mammalian cell models, and total estrogenic (E) and androgenic (A) activity and endogenous hormone levels in plasma from exposed populations (Aims 4- 5). Our preliminary data show that TCE increases E but not A activity in exposed males probably through aromatase induction. Our overall goal is to understand the dose-dependent effects of key Superfund chemicals on steroid hormone pathways, to support comprehensive and cumulative risk assessment.

项目 2：总结/摘要 砷、苯、三氯乙烯 (TCE)、甲醛和多环芳烃 (PAH) 可能 与血液毒性或癌症诱导所需的剂量相比，具有内分泌干扰作用。 有一些证据表明它们可以调节皮质类固醇和性行为中的类固醇激素水平 类固醇途径，可能导致多种不良健康影响。在这里我们建议检查 这些常见的超级基金污染物对糖皮质激素和性类固醇激素的破坏作用 它们对体外细胞系、小鼠体内的组织特异性作用，也许最重要的是在 人类拥有良好的 特征暴露。内源性皮质醇是响应压力而产生的，并作用于糖皮质激素 受体（GR）触发代谢和其他干扰。环境化学物质也会影响GR 途径并被定义为“应激源”。砷就是一个例子，它会改变 GR 信号传导，但 这种影响表达 GR 的不同细胞类型的机制尚不清楚。累积风险评估 消除非遗传环境压力是 EPA 的首要任务，我们已经开发了新的方法来实现这一目标 在暴露范式下。我们的第一个中心假设是砷是一种改变 GR 的应激源 单独或与其他化学物质结合使用时的活性，具有组织特异性的生物学后果。我们 建议使用暴露体方法来了解砷的剂量依赖性影响，单独使用和混合使用 与其他超级基金污染物结合，影响肝脏、脂肪细胞和血液中的糖皮质激素途径 体外细胞；在小鼠体内；以及暴露在外的人类（目标 1-3）。我们将使用灵敏的 GR 活性生物测定 筛选改变 GR 活性的 Superfund 污染物，并测量总糖皮质激素 (G) 活性 来自暴露细胞的培养基和来自暴露于砷的受试者的少量人血浆。使用 直接用血浆进行 GR 生物测定是新颖的。我们的初步筛选数据表明砷是GR 拮抗剂和多环芳烃苯并(a)芘的激动剂。砷以及三氯乙烯、苯、甲醛和 多环芳烃还可能通过调节天然雌激素和雄激素性别而对生殖产生不利影响 荷尔蒙。因此，我们的第二个中心假设是这些污染物调节雌激素受体 (ER) 通过改变天然性激素水平来调节雄激素受体（AR）活性。我们将筛选化学效应 在经过验证的哺乳动物细胞模型中产生这些激素（类固醇生成），以及总雌激素 (E) 和雄激素 (A) 活性以及暴露人群血浆中的内源激素水平（目标 4- 5）。我们的初步数据表明，TCE 可能通过以下方式增加暴露男性的 E 活性，但不增加 A 活性： 芳香酶诱导。我们的总体目标是了解超级基金关键化学品的剂量依赖性影响 类固醇激素途径，以支持全面和累积的风险评估。