Polyethylene Nanoplastic Exposure Causes Miscarriage by Impairing Trophoblast NAD + Metabolism via Mitochondrial Dysfunction

ABSTRACT Micro‐ and nanoplastics (MNPs) are emerging environmental pollutants of global concern, yet their reproductive toxicity and underlying mechanisms remain poorly understood. Here, we identify villous accumulation of polyethylene (PE) as a potential risk factor associated with miscarriage and investigate the underlying mechanisms using well‐characterized PE nanoparticles. PE fragments were detected in all examined human villous tissues and higher levels of these fragments showed a positive association with miscarriage risk (OR = 1.13, 95% CI, 1.00–1.28). In mice, oral exposure to PE‐MNPs led to dose‐dependent embryo resorption. In trophoblasts, PE nanoplastics (PE‐NPs) were efficiently internalized and subsequently impaired cell migration and invasion. Mechanistically, PE‐NPs accumulated within mitochondria, causing structural damage, downregulation of nicotinamide phosphoribosyltransferase (NAMPT), and depletion of nicotinamide adenine dinucleotide (NAD + ), which in turn suppressed fibroblast growth factor 2 (FGF2) expression, resulting in impaired trophoblast migration and invasion. Supplementation with mitochondria‐protective peptide, NAD + or FGF2 attenuated trophoblast dysfunction and reduced embryo resorption. These findings provide mechanistic insight into PE‐NPs‐induced reproductive toxicity and suggest a potential therapeutic target to mitigate the impact of NPs exposure on maternal‐fetal health.