Sulfamethoxazole induces brain capillaries toxicity in zebrafish by up-regulation of VEGF and chemokine signalling

Sulfamethoxazole (SMX) is a widespread broad-spectrum bacteriostatic antibiotic. Its residual is frequently detected in the water and may therefore bioaccumulate in the brain of aquatic organisms via blood circulation. Brain capillaries toxicity is very important for brain development. However, little information is available in the literature to show the toxicity of SMX to brain development. To study the SMX's brain toxic effects and the related mechanisms, we exposed zebrafish embryos to SMX at different concentrations (0 ppm, 1 ppm, 25 ppm, 100 ppm and 250 ppm) and found that high concentration (250 ppm) of SMX would not only caused an abnormal in malformation rate, hatching rate, body length and survival rate of zebrafish embryos, but also lead to brain oedema. In addition, SMX also induced cerebral ischaemia, aggravates oxidative stress, and changes genes related to oxidative stress (sod1, cat, gpx4, and nrf2). Furthermore, ischaemia caused by SMX could promote ectopic angiogenesis in brain via activating the angiogenesis-related genes (vegfab, cxcr4a, cxcl12b) from 24 h to 53 h. Inhibition of VEGF signalling by SU5416, or inhibition of chemokine downstream PI3K signalling by LY294002, could rescue the brain capillaries toxicity and brain oedema induced by SMX. Our results provide new evidence for the brain toxicity of SMX and its residual danger in the environment and aquatic organisms.