Gabapentin Impairs Visual Development in Zebrafish via Retinal Apoptosis and Thyroid Disruption

Abstract

Gabapentin (GBP), a pharmaceutical widely used for seizures and neuropathic pain, has emerged as a contaminant in global aquatic environments, raising concerns about its ecological impact. This study investigated the effects of environmentally relevant concentrations of GBP (0, 1, 10, 1000 μg/L) on visual development in zebrafish (Danio rerio). Behavioral assays showed that GBP exposure enhanced light sensitivity, as indicated by a significant increase in total travel distance (TTD) in all exposure groups compared to controls. The 1 μg/L and 1000 μg/L exposure groups demonstrated a 41% and 37% increase in TTD, respectively (p < 0.05). Apoptosis assays revealed dose-dependent retinal cell death, with fluorescence intensity rising by 15% at 1000 μg/L (p < 0.05). Visual acuity, measured through optokinetic response (OKR) tests, decreased significantly across all color stimuli. Angular velocity under white light decreased from 4.0 °/s in controls to 1.6 °/s at 1000 μg/L (p < 0.01) in a dose-dependent manner. Retinal histopathology showed a 17% increase in ganglion cell layer thickness at 1000 μg/L (p < 0.05) in a dose-dependent manner. Thyroid hormone assays indicated significant reductions in T3 and T4 levels (p < 0.001), with a 22% increase in the T3/T4 ratio at 1000 μg/L. Gene expression analysis revealed dysregulation in apoptosis (casp3a, ifi27), thyroid (tshr, dio1), and retinal development (atoh7, pax6a) pathways. These findings demonstrate that GBP disrupts visual development in zebrafish through retinal apoptosis and thyroid hormone dysregulation, highlighting the ecological risks posed by pharmaceutical pollutants. GBP exposure increased light-driven locomotor activity, indicating heightened light sensitivity due to apoptosis in the retina. Visual acuity was assessed through the optokinetic response (OKR) test, retinal morphology, and thyroid hormone (TH) levels. Even at concentrations as low as 1 µg/L, GBP exposure led to significant reductions in OKR across various colors, likely due to changes in retinal thickness linked to thyroid hormone disruption. These effects were consistent with alterations in gene expression related to apoptosis, the thyroid system, and retinal development. Our findings enhance understanding of how GBP exposure impairs vision in fish and highlight the need to evaluate the ecological risks of pharmaceutical contaminants in aquatic environments.