Developmental toxicity and skin sensitization potential of synthetic phenolic antioxidants and butylated hydroxytoluene transformation products: Insights from human embryonic stem cell models

Synthetic phenolic antioxidants (SPAs) are commonly used in food, cosmetics, and other products for their antioxidant properties and stability. However, increasing evidence links excessive SPA use to adverse effects, including developmental issues in animals. Given the widespread use of SPAs in cosmetics, there is a growing need to assess their potential health risks, particularly whether safe to be used during pregnancy. This study investigates the early developmental toxicity of SPAs using a human embryonic stem cell (hESC) monolayer differentiation model. Results show that SPAs and butylated hydroxytoluene transformation products (BHT-TPs) up-regulated neural ectoderm and neural crest genes while down-regulated surface ectoderm and primitive streak genes during differentiation. Furthermore, in a skin-specific differentiation model, SPAs and BHT-TPs disrupted keratinocyte differentiation, inhibiting the differentiation of keratinocyte progenitors into more mature keratinocytes. They also led to the up-regulation of genes associated with psoriasis, pro-inflammatory cytokines, and chemokines, suggesting the potential of SPAs to act as skin sensitizers. These findings suggest that SPAs may affect early embryonic development at an early germ layer specification stage, as well as during skin development, potentially increasing skin sensitivity. Thus, excessive SPA use in cosmetics could pose risks to fetal development and adult skin health.