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，但只有一个