Abstract
Gut microbiome communicates with the host liver to modify hepatic xenobiotic biotransformation and nutrient homeostasis. Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants that are detected in fatty food, household dust, and human breast milk at worrisome levels. Recently, long noncoding RNAs (lncRNAs) have been recognized as novel biomarkers for toxicological responses and may regulate the transcriptional/translational output of protein-coding genes (PCGs). However, very little is known regarding to what extent the interactions between PBDEs and gut microbiome modulate hepatic lncRNAs and PCGs, and what critical signaling pathways are impacted at the transcriptomic scale. In this study, we performed RNA-Seq in livers of nine-week-old male conventional (CV) and germ-free (GF) mice orally exposed to the most prevalent PBDE congeners BDE-47 and BDE-99 (100 μmol/kg once daily for 4-days; vehicle: corn oil, 10 ml/kg), and unveiled key molecular pathways and PCG-lncRNA pairs targeted by PBDE-gut microbiome interactions. Lack of gut microbiome profoundly altered the PBDE-mediated transcriptomic response in liver, with the most prominent effect observed in BDE-99-exposed GF mice. The top pathways up-regulated by PBDEs were related to xenobiotic metabolism, whereas the top pathways down-regulated by PBDEs were in lipid metabolism and protein synthesis in both enterotypes. Genomic annotation of the differentially regulated lncRNAs revealed that majority of these lncRNAs overlapped with introns and 3’-UTRs of PCGs. Lack of gut microbiome profoundly increased the percentage of PBDE-regulated lncRNAs mapped to the 3’-UTRs of PCGs, suggesting the potential involvement of lncRNAs in increasing the translational efficiency of PCGs by preventing miRNA-3’-UTR binding, as a compensatory mechanism following toxic exposure to PBDEs. Pathway analysis of PCGs paired with lncRNAs revealed that in CV mice, BDE-47 regulated nucleic acid and retinol metabolism, as well as circadian rhythm; whereas BDE-99 regulated fatty acid metabolism. In GF mice, BDE-47 differentially regulated 19 lncRNA-PCG pairs that were associated with glutathione conjugation and transcriptional regulation. In contrast, BDE-99 up-regulated the xenobiotic-metabolizing Cyp3a genes, but down-regulated the fatty acid-metabolizing Cyp4 genes. Taken together, the present study reveals common and unique lncRNAs and PCG targets of PBDEs in mouse liver, and is among the first to show that lack of gut microbiome sensitizes the liver to toxic exposure of BDE-99 but not BDE-47. Therefore, lncRNAs may serve as specific biomarkers that differentiate various PBDE congeners as well as environmental chemical-mediated dysbiosis. Coordinate regulation of PCG-lncRNA pairs may serve as a more efficient molecular mechanism to combat against xenobiotic insult, and especially during dysbiosis-induced increase in the internal dose of toxicants.
Highlights
Polybrominated diphenyl ethers (PBDEs) are flame retardants with widespread application in plastics, rubbers, furniture, and electronic devices
BDE-47 and BDE-99, which are the predominant PBDE congeners detected in human fluid and fatty diet [6], have been shown to activate the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in rodent livers and human hepatocytes, leading to up-regulated expression of the major drug-metabolizing enzymes cytochrome P450s (Cyps) and other genes involved in xenobiotic biotransformation [7,8,9]
We have recently shown that the lack of gut microbiome alters the basal expression of many Cyps and other drug-processing genes (DPGs) in liver, and there is a novel interaction between oral exposure to PBDEs and gut microbiome in modulating the host xenobiotic biotransformation pathways in mouse liver [11, 12]
Summary
Polybrominated diphenyl ethers (PBDEs) are flame retardants with widespread application in plastics, rubbers, furniture, and electronic devices. Liver is a major organ for xenobiotic biotransformation, and increasing evidence in the literature has demonstrated that gut microbiome is a novel frontier for drug metabolism and it communicates with the host liver to fine-tune the efficacy and toxicity of many xenobiotics. We have recently shown that the lack of gut microbiome alters the basal expression of many Cyps and other drug-processing genes (DPGs) in liver, and there is a novel interaction between oral exposure to PBDEs and gut microbiome in modulating the host xenobiotic biotransformation pathways in mouse liver [11, 12]. As a first step to understand the regulation of various metabolic pathways by PBDE-gut microbiome interactions, we used RNA-Seq as a transcriptomic approach to unveil the targeted PCGs in a high-throughput manner
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