Trace-level Gabapentin can induce cardiovascular developmental toxicity through apoptosis in zebrafish larvae

Gabapentin (GBP), an antiepileptic drug to treat epilepsy and neuropathic pain, has become an emerging pollutant in aquatic environments. Previous results suggested that GBP can cause a potential toxicity on the heart development of zebrafish but its cardiovascular effects are still not clear. In the current study, zebrafish embryos were exposed to GBP at environmental relevant concentrations (0, 0.1, 10 and 1000 μg/L) to assess its impact on cardiovascular systems during the early life stage of zebrafish. GBP exposure induced an increase in heartbeat rate and blood flow. The development of blood vessels was also affected with the vascular width significantly decreased at 10 μg/L and higher concentration of GBP. GBP exposure led to an abnormal vascular development by inhibiting the expression of relevant genes (flk1, vegfr-3, gata1, vegfα, and vegfr-2). Furthermore, GBP at 0.1 μg/L elevated the levels of reactive oxygen species and antioxidant enzyme. The vascular cell apoptosis was promoted through genes like p53, bad, and bcl2. However, these adverse effects were reversible with the antioxidant N-acetyl-L-cysteine, highlighting the crucial role of oxidative damage in GBP induced vascular toxicity. This research offers new perspectives on the adverse outcome pathways of antiepileptic drugs in non-target aquatic organisms.