# Environmental drivers of trinucleotide repeat instability and Huntington's disease onset

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $243,000

## Abstract

PROJECT SUMMARY
Trinucleotide repeat disorders is a class of neurological diseases defined by repetitive changes in DNA. Many
trinucleotide repeat disorders including Huntington’s disease (HD), a rare and fatal neurodegenerative disease,
are inherited. HD is caused by expanded repeats of the CAG trinucleotide sequence in the Huntingtin (HTT)
gene. Expansions greater than 36 CAG repeats leads to a pathogenic transcript and proteins causing a late
onset, but severe and terminal form of neurodegeneration. The length of the CAG repeat sequences throughout
the genome is unstable with a high potential to expand across generations. While HD is mostly inherited, a small
proportion of cases arise through sporadic expansion of CAG repeats. Approximately 60% of the variance in the
onset in HD symptoms is attributable to the number of CAG repeats a person carries; more CAG expansions
are associated with earlier onset. Over half of the remaining variability in the duration to symptom onset has
been attributed to environmental factors that remain undiscovered. Environmental chemical exposure could con-
tribute to repeat instability and subsequently, sporadic forms of trinucleotide repeat disorders such as HD. In-
deed, chemical-induced oxidative stress causes CAG repeat expansion mutations. We previously demonstrated
that mitochondria inhibiting pesticides cause oxidative stress in mouse neurons and elicit gene expression sig-
natures of HD. One member of this pesticide class, pyraclostrobin, is applied at very high levels on food to inhibit
fungal pathogens. Predicted human exposure levels suggest that they are sufficient to inhibit human mitochon-
dria and therefore, could contribute to HD disease risk and severity. Our preliminary results demonstrate that
pyraclostrobin causes CAG repeat expansion in cultured cells. We will test the hypothesis that pyraclostrobin
accelerates the course of HD, but is also capable of producing new pathogenic repeat expansions in non-carri-
ers. We will apply a diverse set of molecular, histopathological, and behavioral tools to characterize the HD
phenotypes in a widely accepted mouse model of HD upon pyraclostrobin exposure across the life course. Our
results will provide the foundation necessary to establish prevention strategies for those at familial risk for trinu-
cleotide repeat disorders. Moreover, our work re-defines the role of environmental chemicals as mutagens and
expands their role as contributors to canonical genetic diseases.

## Key facts

- **NIH application ID:** 10193294
- **Project number:** 1R21ES032913-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Brandon L Pearson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2021-04-21 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193294

## Citation

> US National Institutes of Health, RePORTER application 10193294, Environmental drivers of trinucleotide repeat instability and Huntington's disease onset (1R21ES032913-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10193294. Licensed CC0.

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