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.