Natural variation in C. elegans responses to environmental pollution

线虫对环境污染反应的自然变异

• 批准号: 10751120
• 负责人: Tess Catherine Leuthner
• 金额: $ 6.98万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751120
• 关键词: ATAC-seq; Acceleration; Affect; Caenorhabditis elegans; Candidate Disease Gene; Cessation of life; Chemicals; Chromatin; Chromatin Structure; Data; Development; Dimensions; Disease; Environmental Health; Environmental Pollution; Epidemiology; Etiology; Exhibits; Exposure to; Frequencies; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genomic approach; Goals; Half-Life; Health; Health protection; Hour; Immune; Individual; Industrialization; Kidney Diseases; Knowledge; Laboratories; Length; Liver diseases; Malignant Neoplasms; Mediating; Methodology; Mission; Molecular; National Institute of Environmental Health Sciences; Outcome; Pattern; Phenotype; Pollution; Poly-fluoroalkyl substances; Population; Population Growth; Positioning Attribute; Process; Production; Property; Public Health; Quantitative Trait Loci; Regulation; Regulator Genes; Regulatory Pathway; Reproduction; Research; Research Proposals; Resistance; Resources; Risk Assessment; Site; Structure; Structure-Activity Relationship; Technology; Testing; Thyroid Gland; Toxic effect; Toxicity Tests; Toxicology; Transposase; Variant; bioaccumulation; causal variant; chemical safety; consumer product; contaminated drinking water; cooking; drinking; functional genomics; functional group; genetic architecture; genetic variant; genome editing; genome resource; genome wide association study; genomic variation; improved; innovation; insulin signaling; lipid metabolism; mRNA sequencing; multiple omics; novel; novel strategies; pollutant; premature; response; safety testing; transcriptome sequencing

Pollution is the leading environmental cause of premature death and disease globally, yet only a fraction of the hundreds of thousands of chemicals in production have undergone safety testing. To solve this problem, the long-term goal is to develop advanced, predictive toxicity testing to transform environmental health protection. The overall objective of this proposal is to use a groundbreaking population-sequencing approach to harness the natural genetic diversity of wild C. elegans in combination with functional genomics approaches to identify the structure-activity relationships of poly- and perfluoroalkyl substances (PFAS). The central hypothesis is that underlying genetic variation will result in variation in response to PFAS exposures, which will identify unique molecular mechanisms of toxicity across PFAS that vary in three structural properties: chain length, chain composition, and functional group. The rationale is that generating toxicity data to regulate the >12,000 individual PFAS chemicals currently in production is impractical, but identification of structure-activity relationships of PFAS is likely to contribute to improved risk assessment and regulation of PFAS. The central hypothesis will be tested using three specific aims: 1) Determine the contribution of genetic architecture on PFAS toxicity in wild C. elegans; 2) Identify the effects of PFAS structure on gene regulation; and 3) Identify genomic variants that confer sensitivity and resistance to PFAS exposures. For the first aim, 192 wild strains of C. elegans will be used in a pooled-population, selection and sequencing approach to determine the contribution of natural genetic variation in response to exposures and identify quantitative trait loci (QTL) that are associated with specific structural features of PFAS. For the second aim, ATAC-sequencing and mRNA-sequencing will be conducted in laboratory, wild-type (N2) C. elegans following exposures to the same PFAS chemicals to identify gene-regulatory mechanisms involved in response to exposures and shared and unique responses based on each molecular attribute. For the third aim, candidate gene variants will be prioritized and tested for causality (structure-specific sensitivities) using genome editing and phenotypic analysis. This proposal is innovative because it uses a multi- omics approach to identify causal gene variants and regulatory pathways to reveal specific structure- activity signatures of PFAS toxicity. The proposed research is significant because it is expected to contribute to improved risk assessments through the identification of novel mechanisms of PFAS toxicity and structure-activity relationships. Ultimately, the i dentification of genes and molecular mechanisms that mediate response to PFAS exposures provides the opportunity to extrapolate across chemicals that share molecular attributes for improved regulation to promote healthier lives.

污染是全球过早死亡和疾病的主要环境原因，但只有 在生产中的数十万种化学品中，有一部分已经接受了安全测试。至 解决这一问题的长期目标是开发先进的、可预测的毒性测试来转变 环境卫生保护。 这项提案的总体目标是使用一种开创性的 利用野生线虫自然遗传多样性的种群测序法 结合功能基因组学方法鉴定其构效关系 多氟和全氟烷基物质(PFAS)。中心假说是潜在的基因 变异将导致对PFAS暴露的反应的变异，这将识别独特的分子 三种结构性质不同的全氟辛烷磺酸的毒性机制：链长、链 组成和官能团。其基本原理是生成毒性数据来规范 目前生产的12,000种单独的全氟辛烷磺酸化学品是不切实际的，但识别 全氟辛烷磺酸的结构-活性关系可能有助于改进风险评估和 对全氟辛烷磺酸的监管。中心假设将通过三个具体目标进行检验：1)确定 遗传结构对野生线虫全氟辛烷磺酸毒性的贡献；2)确定 PFAS结构对基因调控的影响；以及3)确定赋予敏感性和 对PFAS暴露的抵抗力。在第一个目标中，192个野生线虫菌株将被用于 用混合种群、选择和排序的方法确定自然资源的贡献 暴露反应的遗传变异并确定符合以下条件的数量性状基因座(QTL) 与全氟化肥的特定结构特征相关联。对于第二个目标，ATAC-排序和 将在实验室进行mRNA测序，野生型(N2)线虫在暴露于 相同的PFAS化学物质来识别参与反应的基因调控机制 暴露以及基于每个分子属性的共享和独特的反应。对于第三个目标， 候选基因变异将被优先排序并进行因果关系测试(结构特定的敏感性)。 使用基因组编辑和表型分析。这一建议是创新的，因为它使用了多个 识别致病基因变异和调控途径以揭示特定结构的组学方法- 全氟辛烷磺酸毒性的活性特征。这项拟议的研究意义重大，因为预计它将 通过确定全氟辛烷磺酸的新机制，促进改进风险评估 毒性和构效关系。最终，我 基因和分子的鉴定 调节对全氟辛烷磺酸暴露反应的机制提供了推断 所有具有共同分子属性的化学品都有改进的监管，以促进更健康的生活。