Evaluation of developmental and behavioral toxicity of Resmetirom in zebrafish larvae (Danio rerio)

Resmetirom, a promising oral THR-β agonist for treating metabolic dysfunction-associated steatohepatitis (MASH), has been studied extensively for its therapeutic efficacy, yet its effects on embryonic development remain largely unknown. This study aimed to evaluate the potential embryotoxicity of Resmetirom and investigate its impact on embryonic growth and development. We employed the zebrafish (Danio rerio) as the model organisms, and exposed embryos to varying concentrations of Resmetirom. Key developmental endpoints, including hatchability, mortality, malformation rates, developmental timing, and spontaneous behavior, were systematically assessed. Furthermore, transcriptomic analysis was conducted to elucidate the molecular mechanisms underlying the observed phenotypes. Our findings demonstrated that Resmetirom did not significantly alter hatchability, mortality, or the incidence of morphological malformations. However, exposure to high concentrations (10 μM and 100 μM) induced significant developmental delays and a reduction in spontaneous behaviors. Transcriptomic analysis revealed that Resmetirom exposure dysregulated multiple physiological pathways: the upregulation of a cortisol metabolism-related gene (hsd11b2) may be associated with a shortened stress response; the downregulation of genes critical for fatty acid synthesis (fads2, elovl2) may lead to reduced DHA production and subsequently impair neurodevelopment; suppression of glucose metabolism (gck) could be linked to neuropsychiatric disorders; and the downregulation of a neural function-related gene (gda) may result in neuronal impairment. This study suggests that while Resmetirom may not induce overt teratogenicity, it can cause developmental delays and behavioral abnormalities at high concentrations. These findings provide important initial insights into the potential developmental toxicity of Resmetirom: although acute developmental toxicity is absent, the compound may still impair growth in early life stages and contribute to the onset of depressive symptoms. Such insights not only enhance our understanding of the molecular toxicology of Resmetirom, but also aid in optimizing its clinical application strategies for pediatric and adolescent populations.