Comparative analysis of teratogen-induced malformations and gene expression across zebrafish strains in early development

Zebrafish embryos are widely used in developmental toxicity testing. However, the extent to which genetic background influences susceptibility to teratogenic compounds remains incompletely understood. We here evaluated inter-strain variability in both phenotypic and transcriptomic responses to six model teratogens using five commonly utilized zebrafish strains, AB, TU, RW, WIK, and PET. All test compounds, valproic acid, hydroxyurea, methotrexate, acitretin, topiramate, and ibuprofen, elicited concentration-dependent developmental toxicity characterized by malformations at moderate doses and lethality at higher concentrations. Despite distinct toxicodynamic profiles, the incidence and severity of phenotypic outcomes were highly consistent across strains. Transcriptomic analysis was performed following exposure to valproic acid, hydroxyurea, and warfarin, revealing strong, dose-dependent gene expression changes that were largely conserved among strains. Principal component analysis demonstrated that chemical concentration, rather than strain, was the dominant driver of transcriptional variation. Minor strain-specific differences were observed at baseline or low-dose levels but did not alter the overall direction or magnitude of response. These findings demonstrate that zebrafish embryos from diverse genetic backgrounds exhibit broadly conserved developmental and molecular responses to teratogens. The minimal inter-strain variability supports the use of any wild-type strain, transgenic line, or even outbred population in developmental toxicity testing without compromising sensitivity or reproducibility. Our study reinforces the suitability of zebrafish as a robust vertebrate model in regulatory toxicology.