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

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.