PFAS → PHF8/KDM7B → H3K27me3 → Hox Axis: A Transgenerational Epigenetic Hypothesis of Neurodevelopmental Harm

Per- and polyfluoroalkyl substances (PFAS) are recognized neurotoxicants with transgenerational potential, yet no unified mechanistic model connects their molecular effects with population-level trends such as rising autism spectrum disorder prevalence and declining male fertility. This paper proposes a testable hypothesis: PFAS suppresses the histone demethylase PHF8/KDM7B through cofactor disruption (Fe²⁺ oxidation, α-ketoglutarate depletion, ascorbate exhaustion), leading to persistent H3K27me3 accumulation on Hox gene clusters and impaired retinoic acid signaling.This epigenetic lesion is transmitted transgenerationally via oocyte H3K27me3 (which is not erased during reprogramming) and sperm histone retention at Hox loci. GenX (HFPO-DA) confirms the class effect through its ortholog jmjd-1.2. Five concrete experiments with cost estimates are proposed.