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<p>Tyrosinemia type II (Richner–Hanhart syndrome) is a rare disorder caused by mutations in the TAT gene, leading to elevated blood tyrosine and impaired metabolism. It presents with oculocutaneous symptoms, retinal tyrosine crystals, and neurological issues. Elevated tyrosine disrupts brain metabolism, neurotransmitters, and neurotrophic factors, causing neuroinflammation and affecting brain function. The exact mechanism of neurological damage is unclear, and the impact of dietary intervention on cognition is uncertain. While rodent models are commonly used, zebrafish are emerging as a cost-effective, genetically similar alternative for studying tyrosinemia type II. Thus, this study aims to determine whether acute exposure of zebrafish to elevated tyrosine concentrations can reproduce early central nervous system alterations associated with tyrosinemia type II. Zebrafish were exposed via immersion to 1 mM or 2 mM tyrosine for 1–24&#xa0;h, with a total of 180 animals used across assays. Behavioral analysis was conducted using the novel tank test, and cholinergic and oxidative stress markers were assessed. Brain tyrosine levels were measured centrally. Exposure to 1 mM tyrosine for 24&#xa0;h resulted in the highest brain accumulation, suggesting a non-linear dose-response. Behavioral testing revealed decreased locomotor activity and exploratory behavior, and ChAT activity was reduced in both exposure groups. No significant changes were observed in oxidative stress or protein damage. These findings indicate that acute tyrosine exposure induces early behavioral and cholinergic alterations without detectable oxidative stress, supporting the use of zebrafish as a preliminary model to study early neurochemical disturbances such in tyrosinemia type II. Further studies should explore different life stages, sex-specific responses, chronic exposure, and precise tyrosine kinetics, including potential non-linear effects due to the LAT1 transporter, to clarify mechanisms underlying neurotoxicity and improve translational relevance.</p> Graphical Abstract <p></p>

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Behavioral Alterations and Cholinergic Modulation in Zebrafish Acutely Exposed To Tyrosine

  • 期刊论文

  • 发表日期：

    2025年10月21日

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  • Isabela da Silva Lemos,
  • Francine Fiorot Prando de Vasconcelos,
  • Guilherme da Silva Lodetti,
  • Carolina Giassi Alano,
  • Flávia Karine Rigo,
  • Rahisa Scussel,
  • Fabio Henrique Baia,
  • Eduardo Pacheco Rico,
  • Emilio Luiz Streck

摘要

Tyrosinemia type II (Richner–Hanhart syndrome) is a rare disorder caused by mutations in the TAT gene, leading to elevated blood tyrosine and impaired metabolism. It presents with oculocutaneous symptoms, retinal tyrosine crystals, and neurological issues. Elevated tyrosine disrupts brain metabolism, neurotransmitters, and neurotrophic factors, causing neuroinflammation and affecting brain function. The exact mechanism of neurological damage is unclear, and the impact of dietary intervention on cognition is uncertain. While rodent models are commonly used, zebrafish are emerging as a cost-effective, genetically similar alternative for studying tyrosinemia type II. Thus, this study aims to determine whether acute exposure of zebrafish to elevated tyrosine concentrations can reproduce early central nervous system alterations associated with tyrosinemia type II. Zebrafish were exposed via immersion to 1 mM or 2 mM tyrosine for 1–24 h, with a total of 180 animals used across assays. Behavioral analysis was conducted using the novel tank test, and cholinergic and oxidative stress markers were assessed. Brain tyrosine levels were measured centrally. Exposure to 1 mM tyrosine for 24 h resulted in the highest brain accumulation, suggesting a non-linear dose-response. Behavioral testing revealed decreased locomotor activity and exploratory behavior, and ChAT activity was reduced in both exposure groups. No significant changes were observed in oxidative stress or protein damage. These findings indicate that acute tyrosine exposure induces early behavioral and cholinergic alterations without detectable oxidative stress, supporting the use of zebrafish as a preliminary model to study early neurochemical disturbances such in tyrosinemia type II. Further studies should explore different life stages, sex-specific responses, chronic exposure, and precise tyrosine kinetics, including potential non-linear effects due to the LAT1 transporter, to clarify mechanisms underlying neurotoxicity and improve translational relevance.

Graphical Abstract