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原因，但只有 生产中的数十万种化学品中的一小部分已经过安全测试。到 解决这个问题，长期目标是开发先进的、预测性的毒性测试来转变 环境健康保护。 该提案的总体目标是使用突破性的 利用种群测序方法利用野生秀丽隐杆线虫的自然遗传多样性 结合功能基因组学方法来识别结构-活性关系 多氟烷基物质和全氟烷基物质 (PFAS)。核心假设是潜在的遗传 变化将导致对 PFAS 暴露的反应变化，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 组成和官能团。基本原理是生成毒性数据来调节 目前正在生产的超过 12,000 种 PFAS 化学品是不切实际的，但识别 PFAS 的结构-活性关系可能有助于改进风险评估和 PFAS 的监管。将使用三个具体目标来检验中心假设： 1) 确定 遗传结构对野生线虫中 PFAS 毒性的贡献； 2) 确定影响 PFAS结构对基因调控的影响； 3) 识别赋予敏感性的基因组变异 对 PFAS 暴露的抵抗力。为了实现第一个目标，将使用 192 种野生线虫菌株 汇集群体、选择和测序方法来确定自然的贡献 响应暴露的遗传变异并识别数量性状位点（QTL） 与 PFAS 的特定结构特征相关。对于第二个目标，ATAC 测序和 mRNA 测序将在实验室野生型 (N2) 线虫暴露于 使用相同的 PFAS 化学物质来识别参与响应的基因调节机制 基于每个分子属性的暴露以及共享和独特的反应。为了第三个目标， 候选基因变体将被优先考虑并测试因果关系（结构特异性敏感性） 使用基因组编辑和表型分析。该提案具有创新性，因为它使用了多 组学方法来识别因果基因变异和调控途径以揭示特定结构- PFAS 毒性的活性特征。拟议的研究意义重大，因为预计 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，我 基因和分子鉴定 调解对 PFAS 暴露反应的机制提供了推断的机会 跨越具有共同分子属性的化学物质，以改善监管，促进更健康的生活。