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Ancestral Bisphenol A Exposure Induces Sexually Dimorphic Nonalcoholic Fatty Liver Disease Through Transgenerational Transmission of Sperm Gene Body CpG Island Methylation

ABSTRACT: Environmental exposures induce heritable disease through germline epigenetic alterations, yet how epimutations establish sex-biased metabolic disease in descendants remains unclear. We demonstrate that ancestral bisphenol A (BPA) exposure induces sexually dimorphic nonalcoholic fatty liver disease (NAFLD) in unexposed medaka fish offspring through stable sperm DNA methylation transmission. Females developed severe macrovesicular steatosis with 5,376 differentially expressed genes (DEGs), enrichment for human NAFLD signatures, dysregulated clinically validated biomarkers, and suppressed mitochondrial electron transport chain genes, whereas males showed attenuated microvesicular steatosis with only 306 DEGs. Promoter hypermethylation silenced key hepatic master regulators, HNF4A in females and SREBF1 in males. Whole‑genome bisulfite sequencing revealed twice as many differentially methylated regions (DMRs) in females versus males, enriched in exons, 3′ UTRs, and gene-body CpG-islands versus promoters, indicating non‑promoter‑centric regulation. Critically, 61 gene-body CpG-island DMRs persisted across F0 sperm, F1 sperm, and F2 livers, with mTOR signaling emerging uniquely in F2 liver consistent with nutrient-sensing dysregulation and lipogenesis, while Notch signaling was exclusively enriched in F2 females, aligning with fibrogenic progression. These findings establish gene-body CpG-island methylation as a principal conduit for sex‑specific transgenerational epigenetic inheritance linking ancestral BPA exposure to metabolic liver disease.

ORGANISM(S): Oryzias latipes

PROVIDER: GSE285665 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Purpose: Paternal life experiences impact offspring health via germline, and epigenetic inheritance provides a potential mechanism. However, global reprogramming during offspring embryogenesis and gametogenesis represents the largest hurdle to conceptualize it. Yet, detailed characterization of how sperm epigenetic alterations carrying “environmental memory” can evade offspring embryonic reprogramming remains elusive. Methods: we profiled the sperm DNA methylation patterns of three consecutive generations (F0, F1 and F2) in both control and stress groups by using whole-genome bisulfite sequencing (WGBS). A total of 18 sperm samples were analyzed, including three biological replicates for each generation under each treatment. In addition, small RNA sequencing was carried out on paternal sperm samples to investigate whether long-term psychological stress affected the enrichment of certain sncRNAs and to identify whether they participated in mediating the occurrence and paternal inheritance of the stress-induced DMRs Rsults: Using an optimized data analysis workflow, we obtained approximately 800 million clean reads per sample (build mm10) with strand-specific coverage ~21×, and the data covered ~96.00% of the total 21,867,837 reference CpG dinucleotides. A total of 24,427, 7,975, and 5,173 differentially methylated regions (DMRs) between control and stress groups were found in the F0, F1, and F2 generations, respectively. Inter- and transgenerational inheritance of paternal DMRs were at frequencies approximately 11.36% and 0.48%, respectively. These DMRs related to genes with functional implications for psychological stress response, and tissue inheritance of these DMRs passed paternal disorders epigenetically to offspring. More importantly, these DMRs evaded offspring embryonic reprogramming through erasure and subsequent reestablishment, but not via un-erasure way. Nonetheless, their reestablishment proportions in the primitive streak (E7.5) stage were altered. Furthermore, sncRNA-seq revealed that stress-induced tsRNA, miRNA and rsRNA dysregulation in paternal sperm might play important roles in DMRs occurrence and paternal inheritance.

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Ancestral Bisphenol A Exposure Induces Sexually Dimorphic Nonalcoholic Fatty Liver Disease Through Transgenerational Transmission of Sperm Gene Body CpG Island Methylation

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