NANOS3-YTHDF2 drives aberrant P-body accumulation to impair folliculogenesis in offspring of maternal aristolochic acid I exposure

Processing-bodies (PBs) are cytoplasmic membraneless condensates essential for RNA regulation. They share structural and functional similarities with germ granules and are critical for primordial folliculogenesis, a developmental process highly susceptible to exogenous insults. Aristolochic acid I (AAⅠ), a pervasive environmental toxin from Aristolochiaceae plants, is known to cross the placental barrier and induce fetal ovarian oxidative stress. Here, using a mouse model of maternal AAⅠ exposure (16.5 to 18.5 days post-coitus), we demonstrate that this prenatal insult causes profound defects in offspring folliculogenesis. AAⅠ induces PB enlargement and protein accumulation, causing these condensates to acquire germ granule-like properties. Specifically, AAⅠ upregulates the germ granule component NANOS3 to drive condensate enlargement. Multi-omic profiling further revealed that these aberrant condensates recruit germ granule-associated proteins and exhibit altered RNA profiles. Concurrently, neonatal oocytes exhibited enlarged Balbiani body-like structures alongside intermitochondrial cement, a feature not previously reported in oocytes. Furthermore, AAⅠ promotes the recruitment of N6-methyladenosine (m6A)-related factors into PBs, accompanied by elevated global m6A levels and the upregulation of YTHDF2. We show that YTHDF2 is essential for recruiting NANOS3 to PBs; truncating the intrinsically disordered regions (IDRs) or RNA-binding domains of either protein impairs their interaction. These perinatal perturbations manifest in adulthood as primary ovarian insufficiency (POI)-like dysfunction, including reduced ovarian reserve, compromised oocyte quality, and hormonal deficits. Overall, our work uncovers a NANOS3-YTHDF2 axis that drives germ granule-like PB adaptations, illustrating how fetal environmental insults disrupt folliculogenesis and serve as an etiological driver for adult-onset POI. Female reproductive health depends on the establishment of the ovarian follicle pool before birth, a delicate process highly vulnerable to environmental toxins. This study investigates how Aristolochic acid I (AAⅠ), a widespread, plant-derived toxin that accumulates in the food chain, disrupts folliculogenesis in mice. We found that maternal AAⅠ exposure delayed primordial folliculogenesis in neonatal mouse ovaries. Specifically, AAⅠ abnormally upregulates germline factor NANOS3 and drives the enlargement of processing-bodies (PBs), which regulate RNA metabolism. AAⅠ causes these PBs to recruit germ granule-associated proteins and alters the profiles of PB-associated RNAs. Furthermore, AAⅠ elevates m6A RNA modifications and upregulates the m6A reader YTHDF2. Our cellular assays reveal that YTHDF2 is essential for recruiting NANOS3 into PBs. Most importantly, this neonatal ovarian damage has long-lasting consequences. Female offspring maternally exposed to AAⅠ develop primary ovarian insufficiency (POI)-like dysfunction in early adulthood, characterized by a severely reduced ovarian reserve, poor oocyte quality, and hormonal deficits. Ultimately, our findings illustrate how environmental insults during fetal development can impair female fertility and trigger adult-onset ovarian dysfunction.