Circadian regulation of PAH metabolism

PAH代谢的昼夜节律调节

• 批准号: 9032497
• 负责人: Weston W Porter
• 金额: $ 33.02万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032497
• 关键词: Acute; Affect; African American; Animal Model; Apoptosis; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Behavior; Benzo(a)pyrene; Binding; Biological Process; Biology; Brain; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; Carcinogen Metabolism; Caucasians; Cells; ChIP-seq; Chronobiology; Circadian Rhythms; Cohort Studies; Complex; Cosmic Radiation; DNA Damage; DNA Repair; Disease; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Risk Factor; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Etiology; Genetic; Goals; Health; Hormones; Image; In Vitro; Incidence; Individual; Jet Lag Syndrome; Knockout Mice; Knowledge; Life; Light; Link; MCF7 cell; Malignant Neoplasms; Mammary gland; Measures; Mediating; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitosis; Modeling; Molecular; Mus; National Institute of Environmental Health Sciences; Outcome; Outcomes Research; Pathway interactions; Peripheral; Physiological; Play; Population; Predisposition; Process; Radiation; Reaction Time; Receptor Signaling; Regulation; Research Project Grants; Role; Signal Transduction; Site; Sleep Disorders; Strategic Planning; Testing; Time; Tissues; Toxic effect; Transplantation; Woman; Work; Working Women; benzo(a)pyrene-DNA adduct; cancer initiation; cancer risk; circadian pacemaker; endocrine disruptor exposure; high risk; in vivo; insight; malignant breast neoplasm; mouse model; novel; promoter; prospective; receptor binding; receptor-mediated signaling; shift work; tumor progression

 DESCRIPTION (provided by applicant): The circadian clock plays a key role in coordinating many biological processes from behaviors to cellular metabolism and mitosis. Recent studies have linked disruption of circadian rhythms with increased breast cancer risk, suggesting women working alternative shifts may have a higher risk of breast cancer. Our recent results indicate that disruption of molecular timing negatively impacts several processes that determine the outcome of polyaromatic hydrocarbon (PAH) metabolism, resulting in increased DNA damage. We have found that time of day, as well as individual circadian clock components, uniquely regulate processes governing benzo-a-pyrene (BaP) activated aryl hydrocarbon receptor (AHR) and estrogen receptor (ER) mediated endocrine disruptor (EDC) signaling in the mouse mammary gland and breast cancer cell lines. This new knowledge led us to hypothesize that the circadian clock influences BaP-mediated metabolism and DNA damage and repair, and that time of day, or disruption of the circadian clock, impacts the outcome of PAH exposure and EDC activity. To test this hypothesis we propose two Specific Aims. In Aim 1, we will define the circadian "windows of susceptibility" in mouse mammary tissues and MCF7 breast cancer cells by analyzing differences in BaP-induced AHR- and ER- signaling, formation and persistence of BaP-DNA adducts and DNA damage responses and the time course of BaP clearance using a novel multiphoton imaging approach to measure real time circadian-dependent differences in BaP metabolism in vitro and in vivo. In Aim 2, we will utilize a novel mammary gland transplant approach to discern for the first time in vivo central versus peripheral affects mediating circadia clock influences on acute BaP-induced toxicity and estrogen action in mammary tissues using circadian and AHR and ERa knockout mouse models and binding of AHR and ER in vivo by ChIP-Seq analysis. The expected outcomes of this research will be identification of the key sites of action and metabolic pathways by which PAHs interact with circadian clocks in promoting DNA damage and breast cancer.

 描述（由适用提供）：昼夜节律在协调中起关键作用，从行为到细胞代谢和有丝分裂的许多生物学过程。最近的研究将昼夜节律的破坏与乳腺癌的风险增加联系在一起，这表明妇女的替代转变可能患有更高的乳腺癌风险。我们最近的结果表明，分子时序的破坏对确定多芳烃（PAH）代谢结果的几个过程产生负面影响，从而导致DNA损伤增加。我们发现，一天中的时间以及单个昼夜节律成分，唯一地调节了控制苯并-A-Pyrene（BAP）活化的芳基烃受体（AHR）和雌激素受体（ER）介导的内分泌干扰器（EDC）的过程中的过程。这些新知识使我们假设昼夜节律会影响BAP介导的新陈代谢和DNA损伤和修复，并且一天中的时间或昼夜节律时钟的破坏会影响PAH暴露和EDC活动的结果。为了检验这一假设，我们提出了两个具体目标。在AIM 1中，我们将通过分析BAP诱导的AHR和ER信号，BAP-DNA加合物的形成和持久性，使用新颖的型号的时间差异，使用新型多型循环的时间和时间差异来定义小鼠乳腺组织和MCF7乳腺癌细胞中的昼夜节律“易感性”体内。在AIM 2中，我们将使用一种新型的乳腺移植方法来辨别体内中央与周围的识别，这会影响Circadia时钟对急性BAP诱导的毒性和雌激素作用的影响，并使用AHR和AHR和ERA敲除小鼠模型和Er In In In In In In In In In In In In In In In In In In In In In In In Chip-seq分析。这项研究的预期结果将是识别PAHS在促进DNA损伤和乳腺癌方面与昼夜节律相互作用的关键作用和代谢途径。