Environmental Circadian Disruptors Increase Diabetes and Metabolic Disorders Risk

环境昼夜节律干扰物会增加糖尿病和代谢紊乱的风险

• 批准号: 9145844
• 负责人: Margarita L Dubocovich
• 金额: $ 5.26万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145844
• 关键词: Accounting; Adult; Affect; Affinity; Algorithms; Animal Model; Attenuated; Beta Cell; Binding; Biological Clocks; Blindness; Carbaryl; Cell Proliferation; Cells; Chemicals; Chinese Hamster Ovary Cell; Circadian Rhythms; Computer Simulation; Consensus; Cyclic AMP; Data; Diabetes Mellitus; Diagnosis; Endocrine Disruptors; Endocrine system; Equilibrium; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Fingerprint; Forskolin; Foundations; Future; Gene Expression; Generations; Glucose; Goals; Guanosine Triphosphate; Guidelines; Health; Heart Diseases; Hormones; Human; Hypothalamic structure; In Vitro; Incidence; Insecticides; Insulin; Islets of Langerhans; Kidney Failure; Knockout Mice; Lead; Ligands; Lipid Peroxidation; Lower Extremity; Luciferases; Mammalian Cell; Measures; Mediating; Melatonin; Melatonin Receptors; Metabolic Diseases; Metabolic syndrome; Modeling; Nervous System Physiology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Peripheral; Physiological; Physiological Processes; Physiology; Pineal gland; Protein Kinase C; Rattus; Receptor Signaling; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Reporter Genes; Reproduction; Rest; Risk; Risk Factors; Signal Transduction; Stroke; Structure of beta Cell of islet; System; Testing; Time; Tissues; Toxic Environmental Substances; Withdrawal; Work; base; desensitization; design; diabetes risk; disorder risk; environmental agent; environmental chemical; glucose metabolism; high throughput screening; immune function; in vitro Bioassay; insulin secretion; knowledge base; limb amputation; man; pharmacophore; receptor; receptor binding; receptor function; receptor sensitivity; research study; screening; suprachiasmatic nucleus; three-dimensional modeling; toxicant; virtual

DESCRIPTION (provided by applicant): Exposure to environmental chemicals is a major concern for human health as natural and man-made substances can adversely affect physiological processes which may contribute to the incidence of obesity, metabolic syndrome, and type 2 diabetes. In adults, type 2 diabetes accounts for about 90% of diagnosed diabetes cases and is a major risk factor for heart disease, stroke, kidney failure, non-traumatic lower-limb amputations and blindness. The goal of this proposal is to identify endocrine disruptors affecting the circadian hormone melatonin and its ability to signal "time-of-day" messages to target peripheral tissues. The release of melatonin from the pineal gland is regulated by biological clocks in the suprachiasmatic nucleus (SCN) of the hypothalamus which in turn regulates peripheral target tissues through activation of MT1 and MT2 melatonin receptors. In pancreatic ß-cells, disruption of melatonin receptor signaling may alter homeostatic rhythmic balance of glucose metabolism and insulin release leading to diabetes and metabolic disorders. Our overarching hypothesis is that, certain classes of environmental chemicals act as circadian disruptors by persistent and irregular activation and/or blockade of melatonin receptors in the SCN and in target peripheral tissues (eg. pancreatic islets). Specific aims designed to accomplish our goals are: 1) to use an integrated pharmacoinformatics approach to identify environmental circadian disruptors from a knowledgebase of environmental agents using in silico 2D/3D melatonergic pharmacophore fingerprinting; 2a) to iteratively assess ligand affinity, selectivity and efficacy of environmental disruptors in competition for 2[125I]- iodomelatonin binding to hMT1 and hMT2 melatonin receptors expressed in mammalian CHO cells both in the absence and presence of GTP, and 2b) to modulate forskolin-mediated CRE-luciferase reporter gene expression and insulin secretion via functional activation of rat melatonin receptors expressed in rat INS1 ß-cells; 3) To determine the potential of selected environmental chemicals to alter the rhythmic homeostatic balance of diabetes markers through changes of melatonin receptor sensitivity and signaling in rat INS-1 pancreatic ß-cells (MT1) altering MT1-mediated sensitization and in SCN 2.2 cells by attenuating melatoin- mediated inhibition of cAMP formation (MT1, MT2) and Protein Kinase C stimulation (MT2) using in vitro bioassays. Furthermore, cell proliferation, and lipid peroxidation in pancreatic b-cells will be measured to assess the potential of these disruptors to increase the risk of diabetes associated metabolic disorders. Our integrated Chem2Risk strategy will provide the essential impetus to pursue further testing in animal models and be useful in future assessment of risk factors associated with environmental disruptors carrying similar chemical-structural features and to establish exposure regulatory guidelines.

描述（由申请人提供）：接触环境化学物质是人类健康的一个主要问题，因为天然和人造物质会对生理过程产生不利影响，从而可能导致肥胖、代谢综合征和 2 型糖尿病的发生。在成人中，2 型糖尿病约占诊断糖尿病病例的 90%，是心脏病、中风、肾衰竭、非创伤性下肢截肢和失明的主要危险因素。该提案的目标是确定影响昼夜节律激素褪黑激素的内分泌干扰物及其向目标周围组织发出“一天中的时间”信息的能力。松果体释放褪黑激素受到下丘脑视交叉上核 (SCN) 生物钟的调节，而下丘脑视交叉上核 (SCN) 又通过激活 MT1 和 MT2 褪黑激素受体来调节外周靶组织。在胰腺β细胞中，褪黑激素受体信号传导的破坏可能会改变葡萄糖代谢和胰岛素释放的稳态节律平衡，导致糖尿病和代谢紊乱。我们的总体假设是，某些类别的环境化学物质通过持续且不规则地激活和/或阻断视交叉上核和目标外周组织（例如胰岛）中的褪黑激素受体而充当昼夜节律干扰物。为实现我们的目标而设计的具体目标是：1) 使用综合药物信息学方法，使用计算机 2D/3D 褪黑激素药效团指纹识别技术，从环境因素知识库中识别环境昼夜节律干扰物； 2a) 迭代评估环境破坏剂在竞争 2[125I]-碘褪黑素与 hMT1 和 hMT2 褪黑激素受体（在不存在和存在 GTP 的情况下在哺乳动物 CHO 细胞中表达）结合的配体亲和力、选择性和功效，以及 2b) 通过调节毛喉素介导的 CRE 荧光素酶报告基因表达和胰岛素分泌 大鼠 INS1 β 细胞中表达的大鼠褪黑激素受体的功能激活； 3) 确定选定的环境化学物质通过改变大鼠 INS-1 胰腺 β 细胞 (MT1) 中褪黑激素受体敏感性和信号传导（改变 MT1 介导的致敏作用）和通过减弱褪黑素介导的 cAMP 形成（MT1、MT2）和蛋白激酶 C 的抑制而改变 SCN 2.2 细胞中糖尿病标志物节律稳态平衡的潜力。 使用体外生物测定的刺激（MT2）。此外，还将测量胰腺 b 细胞中的细胞增殖和脂质过氧化，以评估这些干扰物增加糖尿病相关代谢紊乱风险的潜力。我们的综合 Chem2Risk 策略将为在动物模型中进行进一步测试提供必要的动力，并有助于未来评估与具有类似化学结构特征的环境干扰物相关的风险因素，并建立暴露监管指南。