Transcriptomic and epigenetic alterations in aging-related genes in the medaka liver due to ancestral BPA exposure.

Abstract

Environmental endocrine disruptors (EEDs) can accelerate the onset of age-associated liver dysfunction, yet the underlying molecular mechanisms remain poorly understood. Whether unexposed offspring experience differential aging of the liver due to ancestral environmental exposure is currently unknown. Here, we investigated the molecular underpinnings of aging in female medaka livers due to ancestral exposure to bisphenol A (BPA). Exposure occurred at the first (F0) generation, and the aging liver phenotype was examined at the third (F2) generation. Controls did not receive BPA while experimental fish were exposed to 10 μg/L BPA from 8 hours post-fertilization to 15 days post-fertilization, spanning their embryonic and perinatal development during which the liver forms and fully differentiates. The liver developed hepatic steatosis, characterized by increased expression of aging gene signatures commonly found in mice and humans. Transcriptome analysis revealed significant downregulation of 13 mitochondrial oxidative phosphorylation genes, indicating impaired mitochondrial transcriptional activity. A total of 189 aging-associated genes were identified as common between medaka and humans, which are known to regulate mitochondrial metabolism, chromatin remodeling, and inflammation. Functional enrichment linked these changes to oxidative stress, DNA damage, apoptosis, and impaired regenerative capacity. Integrated methylome-transcriptome analysis revealed hypermethylation of gene body CpG islands in core aging regulators, correlating with transcriptional repression and disruption of FoxO, PI3K-Akt, AMPK, and longevity pathways. These findings demonstrate that ancestral BPA exposure induces coordinated mitochondrial, transcriptomic, and epigenetic reprogramming of conserved aging networks, predisposing descendants to accelerated hepatic aging associated with increased severity of sex-biased NAFLD phenotype.