# Novel Mechanisms of Pesticide-Induced Neurotoxicity

> **NIH NIH R01** · IOWA STATE UNIVERSITY · 2020 · $333,663

## Abstract

Abstract
 Environmental exposure to neurotoxic pesticides has been increasingly recognized as a key etiological
factor of sporadic Parkinson’s disease (PD). Despite the established link, deciphering the neurotoxicological
mechanisms associated with chronic pesticide exposure and its role in the etiopathogenesis of PD has been
challenging. Thus, our research proposal intends to explore a novel paradigm in environmental
neurotoxicology by studying the acetylation of histone proteins during pesticide exposure using animal models
of pesticide neurotoxicity. Among various classes of pesticides, exposure to mitochondria-impairing neurotoxic
pesticides, e.g., rotenone, has been linked to the etiology of PD. Mechanistically, exposure to rotenone and
another related pesticide, pyridaben, inhibits mitochondrial complex-1 and impairs proteasomal function in
neuronal cells. Dopaminergic neurons have been shown to be highly vulnerable to rotenone-induced
neurotoxicity. While studying proteasomal dysfunction in mitochondria-impairing pesticide-induced
neurotoxicity, we unexpectedly discovered that rotenone- and pyridaben-induced proteasomal inhibition
resulted in the accumulation of the major histone acetyltransferase enzyme CBP (CREB-binding protein),
which further contributed to acetylation of histones H3 and H4 to promote apoptotic cell death in dopaminergic
neurons. Since hyperacetylation of histones is emerging as a key molecular mechanism capable of producing
long-term changes in gene expression profiles due to chromatin remodeling, we propose to explore this novel
mechanism in the molecular events underlying nigral dopaminergic neuronal damage in chronic mitochondria-
impairing pesticide-induced neurotoxicity models. This work will be accomplished by pursuing the following
specific objectives: i) Map the hyperacetylation sites of core histones H3 and H4 in dopaminergic neuronal
cultures following mitochondria-inhibiting neurotoxic pesticide exposure, ii) Characterize cellular mechanisms
of pesticide-induced hyperacetylation of histones H3 and H4 by examining the contributions of various isoforms
of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and iii) Determine histone acetylation
pattern in chronic rotenone or pyridaben animal models of pesticide neurotoxicity as well as in a progressive
mitochondrial dysfunction-induced transgenic mouse model of PD, confirm the changes in acetylation patterns
and HAT/HDAC homeostasis in human PD brain tissues, and define the functional significance of histone
hyperacetylation-dependent signaling relevant to neurotoxic pesticide-induced neuronal degeneration. Cellular,
molecular and neurochemical approaches will be used to delineate these objectives. Collectively, the proposed
study represents a novel approach in pesticide neurotoxicological research since the work will provide a
comprehensive understanding of the histone hyperacetylation mechanisms pertaining to environmentally-
induced nigral d...

## Key facts

- **NIH application ID:** 9906057
- **Project number:** 5R01ES027245-04
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Anumantha Gounder Kanthasamy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,663
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906057

## Citation

> US National Institutes of Health, RePORTER application 9906057, Novel Mechanisms of Pesticide-Induced Neurotoxicity (5R01ES027245-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906057. Licensed CC0.

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