Perfluorooctanoic Acid Exposure Causes Macrophage Ammonia Retention and Induces Spontaneous Miscarriages

ABSTRACT Spontaneous miscarriage, the most prevalent complication of early pregnancy, poses substantial risks to maternal health worldwide. Perfluorooctanoic acid (PFOA) is a ubiquitous environmental persistent organic pollutant. Human epidemiological studies have linked PFOA exposure to spontaneous miscarriages, yet the underlying mechanisms have been rarely explored. In this study, we found PFOA exposure induced embryonic absorption in pregnant mice by causing ammonia retention in macrophages. Excessive ammonia disrupted mitochondrial function and compromised lysosomal integrity, which ultimately impaired macrophage function. Furthermore, lysosomal dysfunction reduced secretion of cathepsin B (CTSB) and led to decreased macrophage infiltration and diminished trophoblast invasion. Mechanistically, PFOA exposure led to macrophages ammonia retention by promoting the glutaminolysis through the upregulation of glutaminase (GLS) expression. By downregulating the inhibitor of DNA binding protein 3 (ID3), PFOA enhanced nuclear translocation and DNA‐binding affinity of transcription factor 12 (TCF12), which directly activated glutaminase (GLS) transcription to fuel glutamine catabolism. Collectively, our findings delineated a previously unrecognized pathway linking environmental PFOA exposure to spontaneous miscarriage via ammonia‐driven macrophage impairment.