Chronic paternal exposure to low-dose OBS reprograms progeny's intestinal cholesterol metabolism and increases IBD susceptibility.

Sodium p-perfluorous nonenoxybenzenesulfonate (OBS) as a novel alternative to perfluorooctane sulfonate (PFOS) has been extensively used in numerous manufacturing processes, contributing to increasingly grim environmental contamination. Abundant evidence has highlighted the endocrine and metabolic-disrupting properties of OBS, establishing it as an unsafe surrogate for PFOS. However, the intergenerational toxicity of OBS, particularly the impact of paternal exposure on offspring, remains unexplored. Using a murine model, we demonstrated that chronic paternal exposure to low-dose OBS led to gut barrier disruption and heightened susceptibility to dextran sodium sulfate (DSS)-induced colitis in offspring. Through integrated multi-omics analyses including DNA methylome, transcriptome, metagenome, ChIP-seq and metabolome, we uncovered that OBS exposure induced hypermethylation of the Clock promoter in paternal sperm. This epigenetic modification was identified as the causal factor underlying the downregulation of the CLOCK-ABCA1 axis and consequent impairment of cholesterol efflux in offspring colon. Validation using multicolor immunohistochemistry and single-cell transcriptomics in clinical cohorts further substantiated the involvement of the CLOCK-ABCA1 pathway, not only in the disruption of intestinal homeostasis but also in inflammatory bowel disease (IBD) pathogenesis. Collectively, our study provides insight into the intergenerational toxicity of emerging PFAS, which also facilitates the identification of potential targets for the early warning and therapeutic intervention of IBD.