# Natural variation in C. elegans responses to environmental pollution

> **NIH NIH F32** · DUKE UNIVERSITY · 2024 · $69,472

## Abstract

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.

## Key facts

- **NIH application ID:** 10910882
- **Project number:** 5F32ES034954-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Tess Catherine Leuthner
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $69,472
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910882

## Citation

> US National Institutes of Health, RePORTER application 10910882, Natural variation in C. elegans responses to environmental pollution (5F32ES034954-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10910882. Licensed CC0.

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