Thyroid hormone ameliorates ursodeoxycholic acid-induced heart damage in zebrafish embryos

Ursodeoxycholic acid (UDCA) is the most commonly prescribed treatment for intrahepatic cholestasis of pregnancy (ICP) worldwide. Clinical studies show that UDCA helps alleviate maternal pruritus and lowers serum bile acid levels. However, despite treatment, women with ICP still experience unpredictable fetal deaths and other serious pregnancy complications. In this study, we hypothesize that while UDCA improves maternal symptoms, it may have harmful effects on the fetus due to its placental barrier crossing, potentially leading to negative pregnancy outcomes. We found that UDCA concentrations above 150 mg/L can exert toxic effects on zebrafish embryos, including increased mortality, slower heart rates, and pericardial edema. At these concentrations, UDCA also triggered apoptosis and elevated oxidative stress in embryonic cardiomyocytes. Importantly, the thyroid hormone T4 was able to partially mitigate these toxic effects. These findings suggest that adverse pregnancy outcomes in ICP may be related to fetal heart damage caused by UDCA's effects on circulation, providing a possible explanation for fetal death in clinical settings. This also underscores the need to optimize UDCA dosing in clinical practice and explore the use of thyroid hormones as a potential protective therapy for the fetus in ICP cases.