Diquat Induces Cell Death and dopamine Neuron Loss via Reactive Oxygen Species Generation in Caenorhabditis elegans

Diquat (DQ), a contact herbicide extensively utilized
in both agricultural
and nonagricultural domains, exhibits a high correlation with neuronal
disorders. Nevertheless, the toxicity and underlying mechanisms associated
with exposure to environmental concentrations of DQ remain ambiguous.
Here, we report dose-dependent cellular neurotoxicity of DQ in Caenorhabditis elegans. First, DQ significantly compromised
the development and brood size of worms, shortened the lifespan, and
caused epidermal abnormalities. An unbiased transcriptomic analysis
disclosed several pathways related to cell death and peroxisome homeostasis
underlying this organismal-level toxicity. Moreover, exposure of DQ
to C. elegans led to a notable increase
of embryonic cell death. Concurrently, DQ exposure specifically caused
the loss of dopamine neurons but not two other types of neurons in
adulthood, which is in accordance with DQ-induced muscle-related defects
such as pharyngeal pumping, body bends, and head thrashes. Mechanistically,
DQ exposure induces the generation of reactive oxygen species (ROS)
and enhances glutathione-related ROS scavenging pathway. Protein levels
and activities of mitochondrial electron transport chain complexes
were specifically impaired in the DQ-treated worms. Collectively,
this study suggests an ROS-mediated cell death pathway involving the
neuronal and behavioral toxicity of DQ, which offers a novel mitochondria-related
perspective to elucidate the general toxicity caused by a widely distributed
herbicide, DQ, at near-environment concentrations.