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 成千上万种生产化学品中的一部分进行了安全测试。到 解决这个问题，长期目标是开发先进的预测毒性测试以转化 环境健康保护。 该提案的总体目的是使用开创性 利用野生秀丽隐杆线虫的自然遗传多样性的人口序列方法 结合功能基因组学方法，以识别 多氟烷基物质（PFA）。中心假设是潜在的遗传 变化将导致对PFA暴露的响应变化，这将确定独特的分子 跨PFA的毒性机制在三种结构特性中有所不同：链长，链 组成和功能组。理由是生成毒性数据以调节 >目前正在生产的12,000个单独的PFAS化学物质是不切实际的，但鉴定 PFA的结构活动关系可能会导致风险评估的改善和 PFA的调节。中央假设将使用三个特定目的进行检验：1）确定 遗传结构对野生秀丽隐杆线虫中PFAS毒性的贡献； 2）确定 基因调控的PFA结构； 3）确定具有敏感性和的基因组变体 对PFA暴露的抵抗力。为了第一个目标，将使用192个野生曲霉的秀丽隐杆线虫 汇总人口，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确定定量性状基因座（QTL） 与PFA的特定结构特征相关。为了第二个目标，ATAC-severing和 在暴露于实验室的野生型（N2）C。 相同的PFA化学物质以鉴定涉及的基因调节机制 基于每个分子属性的暴露和共享和独特的响应。对于第三个目标， 候选基因变异将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。该建议具有创新性，因为它使用了多种多样的 识别因果基因变异和调节途径以揭示特定结构的方法 - PFAS毒性的活性特征。拟议的研究很重要，因为它有望 通过鉴定PFA的新机制来改善风险评估 毒性和结构活动关系。最终，我 基因和分子的牙齿化 介导对PFAS暴露反应的机制为推断 在共享分子属性的化学物质之间，以改善调节以促进更健康的生活。