ALDH1/2 deficiency modulates dieldrin-induced dopaminergic neurodegeneration and reactive glial morphometry in male mice

Omar A. Yanouri; Adam J. Schuller; Savannah M. Rocha; Aidan M. Briggs; Paul A. Martinez; Elizabeth Fernandez; Randy Strong; Xueshu Li; Hans-Joachim Lehmler; Jonathan A. Doorn; Ronald B. Tjalkens

doi:10.3389/ftox.2026.1888799

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ALDH1/2 deficiency modulates dieldrin-induced dopaminergic neurodegeneration and reactive glial morphometry in male mice

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ALDH1/2 deficiency modulates dieldrin-induced dopaminergic neurodegeneration and reactive glial morphometry in male mice

Omar A. Yanouri, Adam J. Schuller, Savannah M. Rocha, Aidan M. Briggs, Paul A. Martinez, Elizabeth Fernandez, Randy Strong, Xueshu Li, Hans-Joachim Lehmler, Jonathan A. Doorn, …

Frontiers in toxicology, Vol.8, 1888799

09/01/2026

DOI: 10.3389/ftox.2026.1888799

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Abstract

The etiology of Parkinson’s disease (PD) is associated with exposure to environmental contaminants, including the organochlorine pesticide dieldrin. This is thought to occur through induction of oxidative damage and dysregulation of dopamine homeostasis via impairment of aldehyde dehydrogenase (ALDH) enzymes, resulting in neuronal stress that may contribute to glial-mediated neurotoxicity. We postulated that sub-chronic murine dieldrin exposure would induce PD-relevant histopathologic changes in the substantia nigra (SN) which would be exacerbated in ALDH-deficient mice. To test this hypothesis, six-month-old wildtype and Aldh1a1−/− X Aldh2−/− (Aldh1/2 KO) mice were fed dieldrin in chow at doses of 0, 0.2, or 0.6ppm for 6 weeks. Slide scanning microscopy and deep learning-based image analysis were then applied to quantify neuronal injury and glial morphometry. Dieldrin exposure resulted in male-specific dopaminergic neurodegeneration, a dose-dependent increase in astrocytic density, and disease-associated alterations in microglial morphology in the substantia nigra. Interestingly, Aldh1/2 KO attenuated neuronal loss and distinctly modulated reactive astrocytosis and microglial morphometric changes. These results highlight a sex-dependent susceptibility to dieldrin-induced neurotoxicity and suggest a role of ALDH in modulating glial reactivity in the context of PD-like neurodegeneration.

dieldrin

microglia

neurodegeneration

organochlorine

Parkinson’s disease

pesticide

Details

Title: Subtitle: ALDH1/2 deficiency modulates dieldrin-induced dopaminergic neurodegeneration and reactive glial morphometry in male mice
Creators: Omar A. Yanouri - Colorado State University
Adam J. Schuller - Barrow Neurological Institute
Savannah M. Rocha - Colorado State University
Aidan M. Briggs - Barrow Neurological Institute
Paul A. Martinez - The University of Texas at San Antonio Health Science Center
Elizabeth Fernandez - Geriatric Research Education and Clinical Center
Randy Strong - The University of Texas at San Antonio Health Science Center
Xueshu Li - University of Iowa, Occupational and Environmental Health
Hans-Joachim Lehmler - University of Iowa
Jonathan A. Doorn - University of Iowa
Ronald B. Tjalkens - Colorado State University
Resource Type: Journal article
Publication Details: Frontiers in toxicology, Vol.8, 1888799
DOI: 10.3389/ftox.2026.1888799
ISSN: 2673-3080
eISSN: 2673-3080
Publisher: Frontiers Media S.A
Language: English
Date published: 09/01/2026
Academic Unit: Public Health Administration; Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9985225901502771

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