Polychlorinated Biphenyl Exposure Alters tRNA Transcriptome in High-Fat Diet-Fed Mouse Liver

Abstract

Background/Objectives: Exposure of high-fat diet (HFD)-fed mice to polychlorinated biphenyls (PCBs) results in metabolic dysfunction-associated steatotic liver disease (MASLD) and progression to metabolic dysfunction-associated steatohepatitis (MASH). The mechanisms by which HFD diet and PCBs increase MASLD are unclear. Previously, we identified differences in HFD-fed mouse liver tRNA modifications with single oral exposures to the dioxin-like PCB126, the non-dioxin-like PCB mixture Aroclor 1260 (Ar1260), or the combination of Ar1260 + PCB126. Methods: Here, we used small RNA sequencing and the tRNA analysis of expression (tRAX) pipeline to examine if PCB exposures alter the tRNA transcriptome, including tRNA-derived fragments (tRFs), in the livers of the PCB-exposed mice. Results: Each PCB exposure produced distinct hepatic tRNA transcriptomes with more tRNAs decreased than increased. Only tRNA-Glu-TTC-1 was reduced with all three PCB exposures. More changes in tRFs were identified with Ar1260 alone or in combination with PCB126 than with PCB126 alone. Four tRF-3s were upregulated in both PCB126 and Ar1260 + PCB126 co-exposed mice, suggesting PCB126 as responsible for this increase. We previously reported that PCB126 exposure increased hepatic Angiogenin (ANG) protein which generates tRF-3s. Four previously reported tRNA modifications corresponded to positions of PCB-associated tRNA modifications identified by tRAX: m1A, m6A, ms2t6A, and Ψ. Conclusions: Overall, the differences in hepatic tRNAs and tRFs with three different PCB exposures suggest that PCB exposures play an unexplored role in regulating translation in mouse liver.

Keywords: MASLD; PCBs; tRNA.

Figure 1

Read distribution of tRNA isotypes in the livers of the HFD-fed mice exposed to PCBs (A) and the impact of PCB exposures on differential tRNA abundance (B). All mice were fed a HFD. In A, HFDcontrol are data from the livers of the HFD-mice treated with vehicle control(corn oil); HFDAro indicates data from the HFD + Ar1260-exposed livers, HFDPCB indicates data from HFD + PCB126-exposed livers, and HFDAroPCB indicates data from the HFD + Ar1260 + PCB126 co-exposed livers samples. (B) The colors red and green indicate increased or decreased tRNA expression respectively in the samples as indicated. The Venn diagram was finalized using BioRender.com (accessed on 27 March 2025).

Figure 2

The impact of PCB exposures on tRNA-antisense abundance. The colors red and green indicate increased or decreased tRNA-antisense expression in the liver samples as indicated. The data are in the Supplementary Tables S1–S3. The Venn diagram was finalized using BioRender.com (accessed on 27 March 2025).

Figure 3

The impact of PCB exposures on differential tRF abundance in HFD-fed mouse liver. The colors red and green indicate increased or decreased tRF abundance, respectively, in the liver samples as indicated. The data are in the Supplementary Tables S1–S3. The Venn diagram was finalized using BioRender.com (accessed on 27 March 2025).

Figure 4

Association of changes in the abundance of tRNAs and tRFs in HFD-fed mouse liver with PCB exposures. These are tRNAs and tDRs that were differentially expressed in HFD-control versus the indicated PCB exposures. (A) Ar1260 exposure; (B) PCB126 exposure; (C) Ar1260 + PCB126 coexposures. The colors red and green indicate increased or decreased tRNA expression in the samples as indicated. * indicates the same directional change(increased or decreased) of the corresponding tRF(Table 4, Table 5 and Table 6).