Bivalency Erosion as a Unified Mechanism of Inter- and Transgenerational PFAS Neurotoxicity. A Literature Synthesis and Testable Hypothesis (Revised)

This revised hypothesis proposes bivalency erosion as a unified mechanism linking PFAS exposure to inter- and transgenerational neurodevelopmental toxicity. Classical PFAS (PFOA, PFOS) generate functional nuclear Fe2+ deficiency through iron redistribution into mitochondria and lysosomes, impairing Fe(II)-dependent JmjC demethylases while simultaneously suppressing MLL/SET1 writers at the transcriptional level. The result is coordinated loss of H3K27me3 and H3K4me3 at bivalent HOX promoters, producing stochastic resolution subsequently consolidated into directional epigenetic silencing via DNMT3A. The model integrates eleven convergent lines of evidence from twelve laboratories across five species. It is falsifiable via ChIP-seq at HOX loci with dose-response and ascorbate rescue. This is a theoretical literature synthesis containing no original experimental data. Revised edition correcting substrate attribution error in v1