Omics · study · 2026
Ancestral Bisphenol A Exposure Induces Sexually Dimorphic Nonalcoholic Fatty Liver Disease Through Transgenerational Transmission of Sperm Gene Body CpG Island Methylation
Listed in NCBI GEO
Environmentally induced heritable disease phenotypes involve intergenerational transmission of germline epigenetic alterations (epimutations), yet how epimutations establish a sex-biased metabolic disease in descendants remains unclear.
Description
Here, we demonstrate using bisphenol A as an environmental stressor and medaka as an organismal model that environmentally induced heritable sexually dimorphic nonalcoholic fatty liver disease (NAFLD) involves intergenerational transmission of stable sperm DNA methylation memories.
Environmental stress was pronounced in females which included 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 accompanied silenced key hepatic master regulators, HNF4A in female livers and SREBF1 in male livers.
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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, intergenerational sperm analysis revealed 61 gene-body CpG-island DMRs persisting 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 environmental stressor to liver disease.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE285nnn/GSE285665 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE285665 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1205395 ncbi.nlm.nih.gov/bioproject/PRJNA1205395 ↗
project · from NCBI GEO
- PubMed 41836599 pubmed.ncbi.nlm.nih.gov/41836599 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Methylation profiling by high throughput sequencing
- From keywords
- Life Sciences
- Inferred from text
- Disease 75% · Sequencing 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE285665 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:methylation-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |