Polyhalogenated Carbazole Impairs Dopaminergic Neurons through Dysregulation of Liquid–Liquid Phase Separation in Caenorhabditis elegans

Polyhalogenated carbazoles (PHCZ), persistent environmental contaminants, preferentially accumulate in neuronal tissues. Studies using Caenorhabditis elegans and human neuronal cell lines reveal that PHCZ induce dopaminergic neurodegeneration by promoting liquid–liquid phase separation of α‐synuclein, reducing condensate fluidity, impairing mitochondrial integrity, and activating endoplasmic reticulum stress responses. This newly identified neurotoxicity highlights environmental contributions to neurodegenerative diseases. Abstract Polyhalogenated carbazoles (PHCZ) are emerging organic pollutants derived from a variety of natural and synthetic sources. While PHCZ have raised environmental concerns due to its persistence, bioaccumulation, and widespread distribution, its neuronal toxicity remains largely understudied. Here, the general and neuronal toxicity of PHCZ using the model organism Caenorhabditis elegans (C. elegans) is evaluated. It is found that PHCZ can induce significant dopaminergic neurodegeneration, in addition to exhibiting general toxicity affecting development and male gamete differentiation. Mechanistically, PHCZ promote liquid–liquid phase separation (LLPS) of the Parkinson's disease (PD)‐associated protein α‐synuclein (α‐syn), and reduces the fluidity of the resultant condensate both in vitro and in vivo. PHCZ disrupts general protein homeostasis and specifically activates the unfolded protein response in the ER (UPRER) through the IRE‐1 signaling axis. Moreover, PHCZ impairs mitochondrial functions, providing another mechanistic link to neuronal degeneration. Thus, this study uncovers a hitherto unrecognized neuronal toxicity of PHCZ, which is partly attributed to their capacity to dysregulate LLPS and UPRER, offering new insights into their potential health risks. Polyhalogenated carbazoles (PHCZ), persistent environmental contaminants, preferentially accumulate in neuronal tissues. Studies using Caenorhabditis elegans and human neuronal cell lines reveal that PHCZ induce dopaminergic neurodegeneration by promoting liquid–liquid phase separation of α-synuclein, reducing condensate fluidity, impairing mitochondrial integrity, and activating endoplasmic reticulum stress responses. This newly identified neurotoxicity highlights environmental contributions to neurodegenerative diseases. Abstract Polyhalogenated carbazoles (PHCZ) are emerging organic pollutants derived from a variety of natural and synthetic sources. While PHCZ have raised environmental concerns due to its persistence, bioaccumulation, and widespread distribution, its neuronal toxicity remains largely understudied. Here, the general and neuronal toxicity of PHCZ using the model organism Caenorhabditis elegans ( C. elegans ) is evaluated. It is found that PHCZ can induce significant dopaminergic neurodegeneration, in addition to exhibiting general toxicity affecting development and male gamete differentiation. Mechanistically, PHCZ promote liquid–liquid phase separation (LLPS) of the Parkinson's disease (PD)-associated protein α-synuclein (α-syn), and reduces the fluidity of the resultant condensate both in vitro and in viv o. PHCZ disrupts general protein homeostasis and specifically activates the unfolded protein response in the ER (UPR ER ) through the IRE-1 signaling axis. Moreover, PHCZ impairs mitochondrial functions, providing another mechanistic link to neuronal degeneration. Thus, this study uncovers a hitherto unrecognized neuronal toxicity of PHCZ, which is partly attributed to their capacity to dysregulate LLPS and UPR ER, offering new insights into their potential health risks. Advanced Science, Volume 12, Issue 48, December 29, 2025.