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

  • Chem Biol Interact. 2026 Aug 1:436:112213. doi: 10.1016/j.cbi.2026.112213.
Meihong Guo  1 ,  Songci Yan  2 ,  Yu Tang  2 ,  Liehai Hu  2 ,  Zhengyuan Xu  2 ,  Meng Shao  2 ,  Yuxin Liu  2 ,  Qiuyuan Zhu  3 ,  Xinwei Zhang  3 ,  Yong Wang  2 ,  Dongmei Li  2 ,  Xiaodong Han  2 ,  Lili Zhao  4 ,  Lilin Xiong  5 ,  Jiang Wu  6
Affiliations
  • 1. State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Department of Environment Health, Nanjing Municipal Center for Disease Control and Prevention, Nanjing, 210003, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • 2. State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • 3. Department of Environment Health, Nanjing Municipal Center for Disease Control and Prevention, Nanjing, 210003, China.
  • 4. State Key Laboratory of Materials-Oriented Chemical Engineering, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, 211816, China. Electronic address: [email protected].
  • 5. Department of Environment Health, Nanjing Municipal Center for Disease Control and Prevention, Nanjing, 210003, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China. Electronic address: [email protected].
PMID: 42303205 DOI: 10.1016/j.cbi.2026.112213
Abstract

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.

Keywords
Acid ceramidase-1; Fetal growth restriction; Phenylpyruvic acid; Polystyrene microplastics.
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