Transcriptomic Analysis of Gonadal Adipose Tissue in Male Mice Exposed Perinatally to 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47)

Abstract

For the majority of lipophilic compounds, adipose tissue is traditionally considered as a storage depot and only rarely as a target organ. Meanwhile, abnormalities in adipose tissue physiology induced by chemical exposure may contribute to the current epidemic of obesity and metabolic diseases. Polybrominated diphenyl ethers (PBDEs) are a group of lipophilic flame retardants found in the majority of human samples in North America. Their ability to alter the physiology of adipose tissue is unknown. We exposed pregnant mice to 0.2 mg/kg body weight/day of BDE-47 perinatally. Transcriptomic changes in gonadal adipose tissue were analyzed in male offspring using the RNA-seq approach with subsequent bioinformatic analysis. The expression of genes of coagulation and complement cascade, de novo lipogenesis, and xenobiotic metabolism was altered in response to BDE-47 exposure. The affected molecular network included the following hubs: PPARα, HNF1A, and HNF4. These findings suggest that adipose tissue should be considered a target tissue for BDE-47, in addition to its role as a storage depot. This study also builds a background for a targeted search of sensitive phenotypic endpoints of BDE-47 exposure, including lipid profile parameters and coagulation factors in circulation. Additional studies are needed to investigate the role of PBDEs as an obesogen.

Keywords: BDE-47; PBDE; adipose; complement and coagulation cascade; de novo lipogenesis; genomic; metabolism; obesogen; polybrominated diphenyl ether; transcriptomic.

Figure 1

Heat-map for 758 2-fold differentially regulated genes in mouse gonadal adipose tissue on PND21.

Figure 2

KEGG coagulation and complement cascades pathway. Differentially expressed genes are marked with red stars.

Figure 3

GSEA enrichment plots for transcriptional changes in gonadal adipose tissue of mice exposed perinatally to BDE-47: (A) bile acid metabolism gene set; (B) genes targets of HNF4A; and (C) genes targets of SREBF. GSEA plot legend: 1—running enrichment score for the gene set; 2—vertical lines show where the members of the gene set appear in the ranked list of genes; 3 and 4—ranked list of differentially expressed genes from the most up-regulated (left of each plot) to the most downregulated (right of each plot). Regulation is shown in the heat-bar (3) and in the bar plot (4).

Figure 4

Molecular networks of differentially expressed genes regulated by (A) HNF1A and (B) PPARα.

Figure 4

Molecular networks of differentially expressed genes regulated by (A) HNF1A and (B) PPARα.