# Perinatal BPAF Exposure Reprograms Offspring’s Immune–Metabolic Axis: A Multi-Omics Investigation of Intergenerational Hepatotoxicity

## TL;DR

Exposure to BPAF during pregnancy and birth can cause long-term metabolic and immune issues in offspring through changes in the liver's epigenome.

## Contribution

This study reveals how perinatal BPAF exposure reprograms the immune-metabolic axis via epigenetic changes in offspring.

## Key findings

- Perinatal BPAF exposure caused metabolic syndrome in offspring, including glucose intolerance and hepatic steatosis.
- BPAF exposure altered the hepatic epigenome, affecting regulatory elements marked by H3K27ac.
- The epigenetic changes suppressed interferon-γ responses and activated sterol biosynthesis, disrupting the hepatic metabolome.

## Abstract

Bisphenol AF (BPAF), a prevalent bisphenol A (BPA) substitute, raises concerns due to its environmental persistence and endocrine-disrupting potency. While metabolic effects of direct exposure are documented, its intergenerational consequences remain unclear. Here, we demonstrated that perinatal BPAF exposure induced persistent metabolic syndrome in offspring, including glucose intolerance, hepatic steatosis, and adipose hypotrophy. Integrating multi-omics data, we observed that BPAF exposure shaped offspring’s hepatic epigenome, as demonstrated by genome-wide alterations in H3K27ac-marked regulatory elements. This epigenetic rewiring indicated a dual regulatory effect on transcriptomes that suppressed interferon-γ responses while activating sterol biosynthesis, ultimately perturbating hepatic metabolome, including depleted pantothenate levels and accumulation of pro-inflammatory eicosanoids. Our findings suggest that BPAF may act as a developmental toxicant capable of persistently disrupting the immune–metabolic axis through epigenomic mechanisms, highlighting the need for careful re-evaluation of its use as a BPA substitute in consumer products.