Integrated New Approach Methodologies Reveal the Potential Role of 2,7-Dibromocarbazole in Parkinson’s Disease via Monoamine Oxidase B Inhibition and Dopaminergic Dysfunction

The neurotoxicity of emerging contaminants, polyhalogenated
carbazoles
(PHCZs), is elusive. In this study, we investigated the potential
toxicity of 13 prevalent PHCZs utilizing a network toxicology approach,
which revealed shared molecular targets associated with Parkinson’s
disease (PD). Molecular docking simulations assessed the binding affinities
of these PHCZs for eight key PD-related targets, identifying monoamine
oxidase B (MAOB) as a critical target. Among the dihalogenated PHCZs,
2,7-dibromocarbazole (2,7-BCZ) exhibited the highest binding affinity
to MAOB. Comparative molecular docking and dynamics simulations suggest
that the inhibition of MAOB activity by 2,7-BCZ is a potential initiating
event in PHCZ-induced neurological disorders. In vivo experiments confirmed that 2,7-BCZ exposure highly correlates with
α-synuclein aggregation, a hallmark of PD pathology. Transcriptomic
sequencing of 2,7-BCZ-exposed SH-SY5Y cells, combined with analysis
of public PD microarray data, identified shared transcriptional alterations
in genes including CLSTN2, CBLN1, AGTR1, DLK1, and DDC. By integrating pathways from PD-related targets of PHCZs, differentially
expressed genes in 2,7-BCZ-exposed cells, and public PD data sets,
we further elucidated key biological pathways through which 2,7-BCZ
may contribute to PD pathogenesis, particularly dopaminergic synapse
function and neurodevelopmental regulation. Collectively, this study
not only highlights the potential role of PHCZs in PD, elucidating
the potential biological mechanisms by which PHCZs may exacerbate
PD, but also exemplifies an innovative, animal-sparing approach using
New Approach Methodologies (NAMs) to assess environmental pollutants’
risks in neurodegenerative adverse outcomes.