Bisphenol A modulation of DNA repair triggered by environmental genotoxic stress

双酚 A 对环境遗传毒性应激引发的 DNA 修复的调节

• 批准号: 9188075
• 负责人: Natalie Rose Gassman
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188075
• 关键词: 8-hydroxyguanosine; Address; Adult; Base Excision Repairs; Beverages; Calories; Cell Death; Cell Line; Cell Survival; Cells; Chemicals; Chromosomal Rearrangement; Chromosome abnormality; Cisplatin; Consensus; Coupled; DNA; DNA Damage; DNA Repair; DNA glycosylase; DNA lesion; DNA strand break; Data; Deoxyguanosine; Diabetes Mellitus; Diet; Dietary intake; Disease; Disease Progression; Double Strand Break Repair; Down-Regulation; Environmental Health; Excision; Exposure to; Food; Food Additives; Foundational Skills; Frequencies; Future; Generations; Genomic Instability; Genotoxic Stress; Goals; Health; Human; Human Genome; Inflammation; Lead; Lesion; Link; Longitudinal Studies; Malignant Neoplasms; Mentors; Mentorship; Metabolic; Metabolism; Molecular; Mouse Cell Line; Mutagenesis; Mutagens; National Institute of Environmental Health Sciences; Nature; Nonhomologous DNA End Joining; OGG1 gene; Obesity; Oxidants; Oxidative Stress; Pathway interactions; Phase; Phenotype; Play; Proteins; Reactive Oxygen Species; Research; Research Personnel; Research Technics; Role; Safety; Sampling; Scientist; Single Strand Break Repair; Specificity; Testing; Training; Ultraviolet Rays; Universities; Urine; Work; base; bisphenol A; carcinogenesis; colon cancer cell line; consumer product; cytotoxicity; environmental agent; estrogenic; exposed human population; genotoxicity; homologous recombination; human disease; human tissue; improved; in vitro Assay; in vivo; insight; next generation; novel; oxidative DNA damage; oxidative damage; potassium bromate; protective effect; public health relevance; recombinational repair; repaired; reproductive; response; tumor progression

DESCRIPTION (provided by candidate): Bisphenol A (BPA) is highly prevalent in food and beverage containers, and human exposure is ubiquitous. Current BPA research has assessed the genotoxicity of BPA alone but does not examine its potential to damage DNA in human tissues constantly subjected to a variety of environmental DNA damaging agents, e.g., the food additive potassium bromate, or UV-radiation. To address this critical gap, the proposed study will examine co-exposure of BPA with dietary and environmental DNA damaging agents. Preliminary results indicate that co-exposure of BPA with exogenous oxidants enhances cell survival and suppresses removal of oxidative DNA lesions. The studies proposed will investigate the hypothesis that co-exposure of BPA and environmental DNA damaging agents alters DNA repair capacity and induces BPA genotoxic effects. During the mentored K99 phase, I will characterize the effect of BPA on the removal of oxidative DNA damage by base excision repair. Under the mentorship of Dr. Samuel H. Wilson, a leader in the DNA repair field, I will investigate the mechanism that BPA utilizes to suppress DNA damage recognition and/or excision by the OGG1 DNA glycosylase, responsible for removing the oxidative damage lesion, 8-oxoG. Studies will utilize in vivo and in vitro assays to quantify DNA strand breaks, determine the persistence of 8-oxoG lesions, and identify mechanisms of down-regulation of OGG1 activity. This will establish the working hypothesis that BPA alters DNA repair, and provide the essential training for me to continue as an independent investigator. In the R00 phase, I will extend the studies of the K99 period by examining the specificity of BPA for suppressing base excision repair. Co-exposure of BPA with other DNA damaging agents, like UV-radiation, will be characterized to determine if BPA specifically suppresses removal of 8-oxoG vs. other lesions. During this phase, I will also investigate whether BPA-induced suppression of BER results in genomic instability. I will determine if lesion persistence results in increased mutagenesis and chromosomal rearrangements will be examined to determine if lesion removal is accomplished by stimulation of homologous recombination. The K99 proposal will provide the mentoring and critical research techniques necessary to characterize the effects of BPA alone and BPA in combination with damaging agents on BER. This phase of the project will provide me with the foundation of skills necessary to transition into an independent environmental health investigator at a research university. As an independent investigator, I will continue to investigate the abilit of BPA, other genotoxic agents, and deficiencies in DNA repair to modulate DNA repair capacity, and I will characterize the consequences of these effects on human disease and disease progression. These short- and long-term studies will fulfill the strategic goals of the NIEHS by: 1) understanding of integrated effects of BPA, 2) connecting genotoxicity of BPA with human health implications, and 3) determining the molecular mechanism of the exposure response, and 4) training the next generation of environmental scientists.

描述（由候选人提供）：双酚A （BPA）在食品和饮料容器中非常普遍，人类接触无处不在。目前的双酚a研究仅评估了双酚a的遗传毒性，但没有研究它对人体组织中DNA的潜在损害，这些组织经常受到各种环境DNA破坏剂的影响，例如食品添加剂溴酸钾或紫外线辐射。为了解决这一关键的差距，拟议的研究将检查双酚a与饮食和环境DNA破坏剂的共同暴露。初步结果表明，双酚a与外源性氧化剂共同暴露可提高细胞存活率并抑制氧化DNA损伤的清除。这些研究将探讨双酚a和环境DNA损伤剂共同暴露改变DNA修复能力并诱导双酚a基因毒性效应的假设。在指导的K99阶段，我将描述BPA对通过碱基切除修复去除氧化DNA损伤的影响。在DNA修复领域的领导者Samuel H. Wilson博士的指导下，我将研究BPA用于抑制OGG1 DNA糖基酶对DNA损伤识别和/或切除的机制，OGG1 DNA糖基酶负责去除氧化损伤损伤，8-oxoG。研究将利用体内和体外试验来量化DNA链断裂，确定8-oxoG病变的持久性，并确定OGG1活性下调的机制。这将建立BPA改变DNA修复的工作假设，并为我继续作为一名独立调查员提供必要的培训。在R00期，我将通过检测BPA抑制碱基切除修复的特异性来延长K99期的研究。将双酚a与其他DNA损伤剂（如紫外线辐射）共同暴露，以确定双酚a是否特异性抑制8-oxoG的去除，而不是其他损伤。在这个阶段，我还将研究bpa诱导的BER抑制是否会导致基因组不稳定。我将确定病变持续是否会导致突变增加，并检查染色体重排以确定是否通过刺激同源重组来完成病变去除。K99提案将提供必要的指导和关键的研究技术，以表征双酚a单独和双酚a与破坏剂联合对BER的影响。这个阶段的项目将为我提供必要的技能基础，以过渡到一所研究型大学的独立环境健康调查员。作为一名独立研究者，我将继续研究双酚a、其他基因毒性物质和DNA修复缺陷调节DNA修复能力的能力，并将描述这些影响对人类疾病和疾病进展的后果。这些短期和长期的研究将实现NIEHS的战略目标：1)了解双酚a的综合效应；2)将双酚a的遗传毒性与人类健康的影响联系起来；3)确定暴露反应的分子机制；4)培养下一代环境科学家。