Phenylalanine metabolism as a key pathway in polystyrene microplastics-induced abnormal macrophage polarization: Implications for fetal growth and development.

Microplastics have been known to possess reproductive toxicity and can contribute to adverse pregnancy outcomes; however, their specific impact on the immune microenvironment at the maternal-fetal interface remains unclear. This study revealed that polystyrene microplastics (PS-MPs) accumulate extensively in macrophages at the maternal-fetal interface and promote their polarization toward a pro-inflammatory phenotype, ultimately leading to fetal growth restriction. Proteomic analysis indicated that microplastic exposure significantly enriched proteins associated with phenylalanine metabolism in macrophages. Further assays demonstrated a marked increase in intracellular phenylpyruvic acid levels, suggesting it as a key effector molecule mediating abnormal macrophage polarization in this process. Mechanistically, phenylpyruvic acid binds to acid ceramidase-1 and accelerates its degradation, which subsequently elevates ceramide levels and activates the MAPK/ATF2/COX2 signaling pathway. This cascade upregulates inflammatory factors, ultimately causing dysregulation of maternal-fetal interface macrophages and impaired fetal development. A phenylalanine-restricted diet significantly alleviated PS-MPs-induced aberrant macrophage polarization and fetal growth restriction. This study revealed the PS-MPs-induced adverse pregnancy outcomes through modulation of immune cell fate for the first time, providing a novel metabolic-immune perspective for understanding pregnancy complications associated with microplastics exposure.