Embryotoxic and Oxidative Impact of Dapagliflozin: A Dose‐Dependent Study Using a Chick Embryo Model

The teratogenic potential of dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, widely used in managing type 2 diabetes, remains poorly characterized. This study investigates the dose-dependent developmental effects of dapagliflozin using a chick embryo model to provide critical insights into its safety during early developmental stages. Fertilized eggs were incubated under controlled conditions, and dapagliflozin was administered at concentrations of 1.0-2.5 mg/mL on embryonic Day 3. Morphometric analysis revealed significant reductions in body weight (up to 47%) in higher-dose groups compared to controls, with survival rates declining sharply (40% mortality) in the 2.5 mg/mL group. Histological examination demonstrated hepatic steatosis, pulmonary emphysema, and cardiac inflammation, alongside neural apoptosis and vascular abnormalities. Reactive oxygen species (ROS) levels, measured via DPPH (2,2-diphenyl-1-picrylhydrazyl), superoxide dismutase (SOD), and chloramphenicol acetyltransferase (CAT) assays, results from DPPH assay showed up to 94.7% of radical scavenging activity in heart tissue, while intracellular oxidative stress is confirmed by SOD and CAT assays, implicating oxidative stress as a central mediator of these abnormalities. This study provides the first comprehensive evidence of dapagliflozin's dose-dependent teratogenicity in a nonmammalian vertebrate model. The findings underscore the need for caution in prescribing dapagliflozin during pregnancy and warrant further investigations in mammalian systems to evaluate its potential implications for human health.