Synergistic Developmental Toxicity of Cisplatin and Carboplatin in the Gallus gallus domesticus Embryonic Model

Cisplatin and carboplatin, two frontline platinum-based chemotherapeutics, are limited by toxicity and the emergence of resistance during monotherapy. Combination regimens are increasingly considered, yet their developmental safety profiles remain unclear. Here, we assess the individual and combined developmental effects of these drugs using the Gallus gallus domesticus embryonic model, a sensitive system for teratogenic evaluation. A multiparametric strategy was applied, including morphological assessment, Yolk Sac Membrane (YSM) vasculature analysis, and biochemical profiling of total protein, acetylcholinesterase (AChE), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). Both drugs individually impaired development, but their combination produced a striking synergistic toxicity. Embryos displayed severe craniofacial malformations, somite loss, and neural tube closure failure. YSM analysis revealed marked degeneration in vessel density, network length, branching, and segment number. Biochemically, combination treatment yielded maximal protein accumulation, sharp suppression of AChE and ALP, and a drastic reduction in LDH activity. These findings demonstrate that cisplatin–carboplatin co-exposure disrupts embryonic viability, angiogenesis, differentiation, and neurodevelopment more severely than either drug alone. The results highlight a paradox: while combination therapy may overcome resistance in tumors, it substantially amplifies developmental toxicity. This underscores the need to balance therapeutic gain with embryotoxic risk when designing platinum-based drug regimens. Keywords: Cisplatin, Carboplatin, Synergistic effects, Angiogenesis, Chicken Embryo, Developmental Toxicity