Investigation of 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo)-Induced Neurotoxicity in the Zebrafish Models (Danio rerio)

Abstract

Environmental pollutants have been linked to neurotoxicity and are proposed to contribute to neurodegenerative disorders. Trichloroethylene (TCE) has been identified as an environmental contaminant and a potential risk factor for neurologic diseases. In recent studies, 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo), one of the metabolic compounds of TCE, has been implicated as a potent neurotoxicant in TCE-induced neurotoxicity. In addition, TaClo has been associated with Parkinson’s disease (PD) due to its neurotoxic effects and structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The zebrafish model offers a high-throughput and cost-effective platform for chemical screening and toxicity assessment and is widely used in the study of neurodegenerative diseases. While previous studies have shown that environmentally relevant concentrations of TCE induce neurotoxic effects in developing zebrafish, the specific role of TaClo in zebrafish neurotoxicity remains largely unexplored. Therefore, this dissertation aims to investigate TaClo-induced neurotoxicity and to compare its effects with those of MPTP in zebrafish models. In addition, we sought to elucidate the underlying mechanisms of TaClo toxicity, evaluate its long-term effects following early-life exposure, and explore its potential role in contributing to broader diseases. Using zebrafish models, we demonstrated that early-life exposure to TaClo induces neurotoxicity closely resembling that of MPTP at the larval stage. Moreover, our study demonstrated that early-life exposure to TaClo and MPTP results in long-term neurotoxicity that persists into adulthood. Finally, transcriptomic analysis revealed that TaClo and MPTP utilize distinct molecular pathways to mediate neurotoxicity and contribute to various systemic diseases. These findings underscore the value of zebrafish as a model for studying environmental neurotoxicants, support the potential role of TaClo in neurodegenerative diseases, and emphasize the need to address TCE contamination to mitigate long-term public health risks. Overall, this dissertation advances our understanding of the neurotoxic effects of TaClo, a metabolite of the widespread environmental contaminant TCE, and its similarities and differences with the established neurotoxin MPTP.