Altered splicing factor and alternative splicing events in a mouse model of diet- and polychlorinated biphenyl-induced liver disease

Belinda J Petri; Kellianne M Piell; Banrida Wahlang; Kimberly Z Head; Eric C Rouchka; Juw Won Park; Jae Yeon Hwang; Mayukh Banerjee; Matthew C Cave; Carolyn M Klinge

doi:10.1016/j.etap.2023.104260

Altered splicing factor and alternative splicing events in a mouse model of diet- and polychlorinated biphenyl-induced liver disease

Environ Toxicol Pharmacol. 2023 Oct:103:104260. doi: 10.1016/j.etap.2023.104260. Epub 2023 Sep 7.

Authors

Affiliations

¹ Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA.
² University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA.
³ University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA.
⁴ Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, USA.
⁵ University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; KY INBRE Bioinformatics Core, University of Louisville, USA; Department of Computer Science and Engineering, University of Louisville, Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292 USA.
⁶ Department of Computer Science and Engineering, University of Louisville, Louisville, KY 40292, USA.
⁷ University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292 USA.
⁸ Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA.
⁹ Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA. Electronic address: carolyn.klinge@louisville.edu.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is associated with human environmental exposure to polychlorinated biphenyls (PCBs). Alternative splicing (AS) is dysregulated in steatotic liver disease and is regulated by splicing factors (SFs) and N-6 methyladenosine (m6A) modification. Here integrated analysis of hepatic mRNA-sequencing data was used to identify differentially expressed SFs and differential AS events (ASEs) in the livers of high fat diet-fed C57BL/6 J male mice exposed to Aroclor1260, PCB126, Aroclor1260 + PCB126, or vehicle control. Aroclor1260 + PCB126 co-exposure altered 100 SFs and replicate multivariate analysis of transcript splicing (rMATS) identified 449 ASEs in 366 genes associated with NAFLD pathways. These ASEs were similar to those resulting from experimental perturbations in m6A writers, readers, and erasers. These results demonstrate specific hepatic SF and AS regulatory mechanisms are disrupted by HFD and PCB exposures, contributing to the expression of altered isoforms that may play a role in NAFLD progression to NASH.

Keywords: Alternative splicing; High fat diet; Liver; PCBs; RNA splicing factors.

MeSH terms

Alternative Splicing* / drug effects
Animals
Aroclors / toxicity
Diet, High-Fat* / adverse effects
Disease Models, Animal
Environmental Pollutants / toxicity
Liver* / drug effects
Liver* / metabolism
Liver* / pathology
Male
Mice
Mice, Inbred C57BL*
Non-alcoholic Fatty Liver Disease* / chemically induced
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / metabolism
Polychlorinated Biphenyls* / toxicity
RNA Splicing Factors / genetics
RNA Splicing Factors / metabolism

Substances

Polychlorinated Biphenyls
aroclor 1260
Aroclors
RNA Splicing Factors
Environmental Pollutants
2,3',4,4',5-pentachlorobiphenyl

Abstract

MeSH terms

Substances

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