# Characterization of endocrine signaling and RNAi pathways as mechanisms regulating environmental programming in C. elegans

> **NIH NIH R01** · SYRACUSE UNIVERSITY · 2021 · $300,000

## Abstract

Increasing evidence suggests that fetal and childhood experiences impact adult disease in humans through
changes in tissue-specific gene expression states and sustained altered function of the neuroendocrine HPA
axis. However, the molecular pathways by which environmental cues experienced in utero or early childhood
result in long-lasting effects associated with adult disease, and how they can be inherited over generations, are
not well understood.
 Caenorhabditis elegans nematodes provide a unique animal model system in which to explore the
mechanisms of environmental programming of gene expression due to early experience. Although adult
animals that experienced environmental stress early in development appear grossly identical to animals that
experienced favorable conditions, these adults retain a cellular memory of their environmental history that is
manifested by changes in gene expression and fertility that are distinct for the particular stress experienced.
Animals that experienced early-life starvation exhibited decreased fertility compared to controls, which is
dependent upon the upregulation of conserved endocrine signaling pathways and the CSR-1 RNAi pathway.
Interestingly, these endocrine signaling pathways, steroid hormone signaling and fatty acid metabolism, are
also upregulated in long-lived animals lacking a germ line. In addition, the reduced fertility phenotype of
starvation-stressed animals is also inherited for at least two generations via the HRDE-1 RNAi pathway.
 The overall goal of this proposal is to investigate how pathways that can promote longevity in germline-less
animals can also modulate reproduction in animals that experienced nutritional stress. The specific aims of this
proposal include: 1) investigate the roles of steroid signaling and fatty acid metabolism in the regulation of
fertility after early-life starvation. This aim proposes genetic and biochemical experiments to test the hypothesis
that DAF-12/NHR acts as a “fat sensor” to modulate germ line production based on levels of stored fat by
directly regulating gene(s) with functions in promoting the onset of germline proliferation. 2) Using biochemical
and developmental genetics experiments, test whether the increased fatty acid metabolism in csr-1 hypomorph
adults is due to direct regulation of fat genes by CSR-1 in the intestine, or an indirect effect of reduced fertility
in the csr-1 hypomorph, as germ line defects may trigger these pathways. 3) Determine the mechanisms of
inheritance for reduced fertility in progeny of animals that experienced nutritional stress. Experiments will test
whether steroid signaling and fatty acid metabolism genes are also upregulated in F1 progeny. HRDE-1
associated siRNAs will also be deep sequenced in the progeny to identify target genes contributing to the
reduced fertility phenotype. Together, these experiments will investigate how pathways that promote somatic
longevity in germline-less animals can also modulate fertility ...

## Key facts

- **NIH application ID:** 10170387
- **Project number:** 5R01GM129135-03
- **Recipient organization:** SYRACUSE UNIVERSITY
- **Principal Investigator:** SARAH E HALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $300,000
- **Award type:** 5
- **Project period:** 2019-06-17 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170387

## Citation

> US National Institutes of Health, RePORTER application 10170387, Characterization of endocrine signaling and RNAi pathways as mechanisms regulating environmental programming in C. elegans (5R01GM129135-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10170387. Licensed CC0.

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