# Long-Read Isoform Sequencing Reveals Aroclor1260-Induced Isoform Usage in Mouse Livers

## TL;DR

Exposure to Aroclor1260 changes how certain genes are expressed in mouse livers, contributing to liver disease.

## Contribution

This study is the first to use long-read sequencing to identify differential transcript usage in PCB-induced liver disease.

## Key findings

- Isoform changes in Adpgk, Blvra, Mup2, and Ndufaf6 are linked to metabolic pathways in MASLD.
- PCB exposure alters transcript isoforms of genes involved in lipid metabolism and oxidative stress.
- Network analysis connects these isoform changes to selenoprotein modifications observed in proteomics.

## Abstract

Background/Objectives: Long-term exposure to polychlorinated biphenyls (PCBs), including the mixture of PCBs in Aroclor1260 (Ar1260), results in metabolic dysfunction-associated steatotic liver disease (MASLD) in mice and humans. While the effects of PCBs on gene expression are well-documented using short-read RNA sequencing, the regulatory roles of alternative splicing (AS) and differential transcript usage (DTU) are uncharacterized. AS has been implicated in MASLD. Previously, we reported that chronic (34 wks.) exposure of normal, low-fat-diet (LFD)-fed male mice to Ar1260 resulted in 12 hepatic RNA modifications. Proteomic analysis of these same liver samples identified Ar1260 exposure-associated changes in selenoproteins: GPX4 and SELENBP2 were increased and SELENOS and SELENOF were reduced. Methods: Here we used long-read isoform sequencing (IsoSeq) to identify DTU in four genes in the Ar1260-exposed livers: Adpgk, Blvra, Mup2, and Ndufaf6. Results: Network analysis of the corresponding proteins revealed a strong association with pathways relevant to MASLD including lipid metabolism, glycolysis, and oxidative stress. Conclusions: These findings suggest that PCB exposure alters the transcript isoform landscape of key metabolic genes involved in MASLD.