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，只有一小部分经过了安全测试。到 为了解决这个问题，长期目标是开发先进的、预测性的毒性测试， 环境健康保护。 该提案的总体目标是使用一种开创性的 群体测序方法来利用野生C.优雅在 与功能基因组学方法相结合，以确定结构-活性关系 聚和全氟烷基物质（PFAS）。核心假设是， 变异将导致对PFAS暴露反应的变异，这将识别独特的分子 PFAS的毒性机制在三个结构特性上有所不同：链长，链 组成和功能组。其基本原理是，生成毒性数据以规范 目前生产中的超过12，000种PFAS化学品是不切实际的，但 PFAS的结构-活性关系可能有助于改进风险评估， 规范PFAS。中心假设将使用三个具体目标进行测试：1）确定 遗传结构对野生C.（2）确定影响 PFAS结构对基因调控的影响;以及3）鉴定赋予敏感性和 抗PFAS暴露。第一个目标是，192株野生型C. elegans将被用于 采用混合种群、选择和排序方法确定自然资源的贡献 遗传变异，并确定数量性状基因座（QTL）， 与PFAS的特定结构特征相关。对于第二个目标，ATAC测序和 mRNA测序将在实验室中进行，野生型（N2）C。在暴露于 同样的PFAS化学品，以确定基因调控机制参与响应 暴露以及基于每个分子属性的共享和独特响应。对于第三个目标， 将对候选基因变体进行优先排序并检测因果关系（结构特异性灵敏度） 使用基因组编辑和表型分析。这是一项创新，因为它采用了多... 组学方法，以确定致病基因变异和调控途径，以揭示特定的结构- PFAS毒性的活性特征。这项研究意义重大，因为它有望 通过识别PFAS的新机制，有助于改进风险评估 毒性和构效关系。最终，i 基因和分子鉴定 调节对PFAS暴露的反应的机制提供了外推的机会， 这些化学品具有相同的分子属性，可以改善监管，促进更健康的生活。