Parental-origin-divergent m6A remodeling mediates transgenerational male reproductive toxicity of PFHpA via PPARα-dependent steroidogenic disruption

Short-chain per- and polyfluoroalkyl substances (PFAS), including perfluoroheptanoic acid (PFHpA), are increasingly used as alternatives to legacy PFAS, yet their heritable reproductive toxicity and underlying epitranscriptomic mechanisms remain unclear. We established complementary maternal and paternal PFHpA exposure mouse models and evaluated male reproductive outcomes across generations. Testicular histology, computer-assisted sperm analysis, hormone measurements, MeRIP-seq/RNA-seq, qRT-PCR, Leydig-cell assays, gene perturbation, molecular docking, surface plasmon resonance and PPARα antagonism were integrated to define lineage-specific mechanisms. The results indicated that PFHpA exposure induced testicular structural abnormalities, impaired sperm-related parameters and reduced testosterone production in directly exposed males and unexposed descendants. Maternal and paternal lineages displayed distinct global and transcript-specific m⁶A remodeling patterns, but both converged on lipid metabolism, PPAR signaling and steroidogenic disruption. In the maternal lineage, reduced Mettl3 expression was associated with decreased m⁶A modification and expression of Lpl, and Lpl overexpression partly restored testosterone synthesis in TM3 Leydig cells. In the paternal lineage, increased Rbm15-related m⁶A remodeling was linked to reduced Fabp1 expression in testes and Leydig cells. PFHpA interacted with PPARα in silico and by surface plasmon resonance, and pharmacological PPARα antagonism attenuated PFHpA-induced testosterone reduction. In conclusion, Parental PFHpA exposure produces parental-origin-divergent epitranscriptomic responses that persist across generations but converge on a PPARα-dependent lipid-steroidogenic axis. These findings identify m⁶A remodeling as a mechanistic mediator of short-chain PFAS-induced transgenerational male reproductive toxicity and support stronger consideration of parental origin in PFAS reproductive risk assessment.