Toxicity and cardiac effects of acute exposure to tryptophan metabolites on the kynurenine pathway in early developing zebrafish (Danio rerio) embryos

Defects in tryptophan metabolism on the l-kynurenine pathway (KP) are implicated in a number of human diseases, including chronic kidney disease, brain edema or injury, tuberculosis and malaria - as well as cancer, neurodegenerative and autoimmune disorders. However, it is unclear to what extent detrimental effects of exposure to tryptophan metabolites might impact the early development of organism. Thus, this study examined the effects of KP exposure in zebrafish embryos starting at the blastula period (4hpf) and the segmentation stage (24hpf). 24-hour EC₅₀ and LC₅₀ values were determined in 4hpf embryos as: 26.74 and 331.6μM for anthranilic acid (AA), 62.88 and 616.4μM for quinolinic acid (QUIN), and EC₅₀ - 96.10μM for picolinic acid (PA) and LC₅₀ - 400μM in kynurenic acid (KYNA). In addition, treatment with nanomolar concentrations of KYNA (50nM, 48 and 72hpf embryos) caused a dose-dependent increase in heartbeat. The increase was also seen with l-kyn treatment (50μM, 72hpf), which was the opposite of other applied l-kyn metabolites. A significant drop in heartbeat was observed after a 20-min acute exposure to 626μM PA, 594μM XA and 499μM QUIN, and complete recovery was seen only when PA had been removed. Concentrations of KP metabolites reached in people with different pathological conditions did not exert toxicity to zebrafish embryos and seems to be safe for developing embryos and therefore, the risk of developing impairments in pregnancy of women carrying KP-associated pathologies is initially low.