Developmental Toxicity Evaluation of the Dietary Supplement Vinpocetine Using Mouse and Human 3D Gastruloids

Vinpocetine is marketed as a dietary supplement for cognitive enhancement, despite the absence of regulatory requirements for comprehensive toxicity testing. The FDA has issued a warning against vinpocetine use by individuals of childbearing potential based on animal studies demonstrating impaired embryonic development. However, the relevance of these findings to human embryogenesis, as well as the contribution of vinpocetine's activity as a cyclic nucleotide metabolism modulator, remains unclear. To address these gaps, gastruloids derived from pluripotent stem cells may provide in vitro models of embryogenesis for investigating chemical impacts.

Gastruloids were generated from mouse P19C5 and human H9 pluripotent stem cells to evaluate the effects of vinpocetine, its major metabolite apovincaminic acid, and additional modulators of cyclic nucleotide metabolism. Morphological effects were measured using established morphometric parameters, and molecular effects were evaluated based on a previously validated panel of developmental regulator genes as sensitive biomarkers.

Vinpocetine induced distinct morphological changes in mouse gastruloids at concentrations ≥ 1 μM, whereas apovincaminic acid produced similar effects only at substantially higher concentrations. Other cyclic nucleotide-modulating compounds, including ITI-214, IBMX, forskolin, and cinaciguat, did not phenocopy vinpocetine-induced defects. In human gastruloids, vinpocetine impaired morphogenesis and altered developmental regulator expression at concentrations ≥ 0.2 μM.

Vinpocetine disrupts gastruloid development in both mouse and human models at concentrations commonly used to elicit purported neuroprotective effects, supporting animal-based evidence of developmental toxicity and demonstrating human relevance. These findings highlight reproductive safety concerns associated with vinpocetine and underscore the need for systematic toxicity evaluation of dietary supplements.