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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: 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. 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. 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.

ORGANISM(S): Oryzias latipes

PROVIDER: GSE285665 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Methylated sperm DNA was isolated from rats ancestrally exposed to methoxychlor. Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. Treated samples were paired with control samples and hybridized together on arrays, resulting in three arrays for the treatment.

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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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