# Exposure to the organochlorine pesticide cis-chlordane induces ALS-like mitochondrial perturbations in stem cell-derived motor neurons

## TL;DR

This study shows that exposure to the pesticide cis-chlordane causes mitochondrial damage in motor neurons similar to that seen in ALS, suggesting a potential environmental link to the disease.

## Contribution

The study identifies cis-chlordane as a novel environmental agent that induces ALS-like mitochondrial dysfunction in motor neurons.

## Key findings

- Cis-chlordane exposure leads to increased reactive oxygen species and decreased ATP production in motor neurons.
- The pesticide causes loss of mitochondrial membrane potential and reduced oxygen consumption rate.
- Cis-chlordane-induced mitochondrial changes resemble those observed in ALS patients.

## Abstract

Amyotrophic Lateral Sclerosis (ALS) is a debilitating and incurable neurodegenerative disease with unsolved etiology. Due to the large proportion of patients lacking direct disease inheritance, understanding the environmental factors that contribute to ALS development is of high priority. Epidemiological studies have implicated pesticides and other environmental exposures as possible contributors to ALS pathogenesis. Recently, our group determined that the organochlorine pesticide cis-chlordane is toxic to human motor neurons in a dose-dependent manner, causing an ALS-like phenotype in culture and animals with a mode of action independent of its known GABAA antagonism. Here, we aimed to characterize downstream motor neuron phenotypes associated with cis-chlordane treatment. We performed bulk RNA sequencing, live imaging, immunofluorescent labeling, and real-time metabolic assays on stem cell-derived motor neurons to assess chlordane-associated phenotypes in vitro. We demonstrate that cis-chlordane treatment causes a highly altered mitochondrial phenotype in motor neurons, including increased production of reactive oxygen species, decreased oxygen consumption rate and ATP production, and loss of mitochondrial membrane potential. We further implicate cis-chlordane as a possible mediator of potent motor neuron damage, with exposure to the pesticide inducing mitochondrial phenotypes akin to those seen in ALS. Our findings contribute to the growing body of evidence that future studies of investigating the role of pesticides in ALS development should focus on organochlorine molecules.