Lipid metabolism dysfunction and toxicity of BDE-47 exposure in white adipose tissue revealed by the integration of lipidomics and metabolomics

https://doi.org/10.1016/j.scitotenv.2021.150350Get rights and content

Highlights

  • BDE-47 exposure promoted adipocyte hypertrophy in high-fat diet (HFD) fed mice.

  • BDE-47 exposure with HFD upregulated ceramide-sphingolipid signaling pathway.

  • BDE-47 exposure with HFD increased saturated fatty acids and blocked β-oxidation.

  • BDE-47 increased inflammatory infiltration in adipose tissue in HFD fed mice.

Abstract

2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) is one of the main and toxic congeners of polybrominated diphenyl ether (PBDE) family and considered to be associated with the development of obesity. However, little is known about its direct metabolic alterations on white adipose tissue (WAT). In this study, we evaluated the impacts of BDE-47 exposure on WAT dysfunctions in mice fed with low-fat diet (LFD) or high-fat diet (HFD) by the integration analysis of mass spectrometry-based metabolomics and lipidomics. The results showed that BDE-47 exposure together with HFD intervention induced adipocyte hypertrophy and accelerated the weight gain of WAT, whereas no obvious effects were observed in mice fed with LFD. The combination of BDE-47 and HFD induced intolerable levels of metabolites in purine and glutathione metabolism pathways, sufficient to increase oxidative stress in WAT. Importantly, continuous exposure of BDE-47 in HFD -fed mice caused lipid metabolism dysfunction by promoting fatty acid uptake and de novo synthesis and suppressing β-oxidation, ultimately leading to the accumulation of saturated fatty acids, triglycerides in WAT. At the same time, BDE-47 increased inflammatory infiltration into WAT, consequently promoting the productions of cytokines, TNFα and IL-6, in HFD fed mice. It is found that dysfunction of lipid metabolism and increasing inflammation led to lipotoxicity in WAT and severe obesity in HFD mice. Taken together, our findings deepen the understanding of the obesogenic effect of BDE-47 and help identify new potential strategies for clarifying the molecular and metabolic mechanisms.

Introduction

The prevalence of obesity in the past several decades has drawn great attention and become a major global public health challenge (Blüher, 2019). Obesity is characterized by the excessive expansion and accumulation of white adipose tissue (WAT) in human bodies (Blüher, 2019; Cai et al., 2020). WAT is the central regulator of systemic energy homeostasis as it serves as an energy pool to synthesize and store triglycerides (TGs) for long-term energy demands; at the same time, WAT also releases free fatty acids (FFAs) from TGs for energy support. In addition, WAT plays a role in endocrine regulation for whole-body metabolism through producing adipokines, such as adiponectin and leptin (Rosen and Spiegelman, 2014). The dysfunction of lipid metabolism in WAT may result in lipotoxicity and is closely associated with metabolic diseases, such as type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD) (Carobbio et al., 2017; Longo et al., 2019). Recently, environmental pollutants have been proposed as “obesogens” that could be involved in endocrine metabolism and disturb adipocyte functions to increase the risk of obesity (Yang et al., 2017). Increasing epidemiological evidence indicated that exposure to environmental pollutants, such as persistent organic pollutants (POPs), were positively associated with obesity (Arrebola et al., 2014; Lauritzen et al., 2018). However, little is known about the metabolic alterations and biological mechanisms in WAT for the development of obesity induced by POPs exposure.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants, which were an emerging class of POPs extensively used as flame retardants in various commercial, domestic and industrial products, such as household furniture, electronics, and textiles from the 1970s to early 2000s (Abbasi et al., 2019). As they are not chemically bounded to the matrices where they were added, PBDEs can easily leak out from the products and migrate into surrounding environment. Due to their persistence and potential health risks, penta- and octaBDE were listed as persistent organic pollutants (POPs) in 2009 by Stockholm Convention and banned for usage worldwide (Stapleton et al., 2011). DecaBDE was included on the list since 2017; but it was still produced and used in China (Zhao et al., 2021). Despite the efforts to regulate the use of PBDEs, high levels of PBDEs have been detected in a variety of environmental samples, biota, human serum and tissue because of the persistence and usage of decaBDE in China (Chai et al., 2019; Drage et al., 2019; Ge et al., 2018; J Wang et al. 2018; Yu et al., 2009).

Among the PBDEs, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is one of the most abundant congeners detected in human milk, serum, and adipose tissues (Brasseur et al., 2014; He et al., 2018; Toms et al., 2007). Maternal exposure with BDE-47 was reported to be positively correlated with childhood obesity (Erkin-Cakmak et al., 2015; Warner et al., 2018). Furthermore, serum BDE-47 level was found to be positively corrected with the expression of adipokines in subcutaneous adipose tissue and inflammation in serum, indicating the potential roles played in the regulation of adipose tissue (Pereira-Fernandes et al., 2014). In addition, in utero and lactation exposure to BDE-47 could induce lipid metabolism dysfunction in livers of mouse offspring (D Wang et al. 2018). Our previous studies indicated that BDE-47 exposure not only accelerated adipocyte differentiation with lipid droplets accumulation but also stimulated the development of obesity in high-fat diet (HFD) mice aggravating the NAFLD accompanied by disrupted lipid metabolism in livers (Yang et al., 2018; Yang et al., 2019). However, the effects of BDE-47 exposure on white adipose tissue remain poorly understood. Therefore, the functional role of BDE-47 exposure on adipose tissue need to be explored and investigated for a better understanding of the development of BDE-47-induced obesity and NAFLD.

Mass spectrometry (MS)-based metabolomics is a cutting-edge technique for comprehensive characterizations of metabolites and metabolism in biological systems and widely used in drug discovery, environmental toxicology, and precision medicine (Wishart, 2016; Zhang et al., 2019). Metabolites are small molecules which serve as direct signatures in response to external stimulations; studies of variations of metabolites in relation to contaminant exposure provide unique insights into the fundamental mechanisms of diseases (Patti et al., 2012). Lipids are essential metabolites involved in critical cellular metabolism. Lipidomics, a branch of metabolomics, emerged as a complementary approach for the detection and characterization of lipids and their biosynthetic enzymes in biological systems to better understand cellular lipid metabolism (Han, 2016; Wenk, 2010). An excessive accumulation of WAT with metabolic dysfunction causes lipid spill-over to other organs, such as visceral fat and liver, resulting in lipid toxication and metabolic alterations in these organs (Morigny et al., 2021). Given the critical roles of WAT for whole body energy homeostasis and lipophilic character of BDE-47 resulting in its accumulation in WAT, we hypothesize that BDE-47 exposure may firstly induce lipid metabolism disorders in WAT leading to lipotoxicity and inflammation in the mouse bodies. To investigate the lipid disorders-induced by BDE-47 in WAT, in the present study, we applied MS-based metabolomics and lipidomics strategies. In addition, the phenotype changes, fatty acid composition, gene expressions of lipid metabolism related enzymes and inflammation cytokines were further evaluated to study the underlying mechanisms of the lipotoxicity induced by BDE-47 on C57BL/6J mouse WAT.

Section snippets

Chemicals and reagents

BDE-47 (purity ≥99.0%), dimethylsulfoxide (DMSO), and 1,2-dinonadecanoyl-sn-3-phophocholine (PC 19:0/19:0) were bought from Sigma-Aldrich (St. Louis, MO, USA). SYBR Premix Ex Taq™ (Tli RNaseH Plus) and PrimeScript™ RT reagent Kit (Perfect Real Time) were obtained from Takara Biotechnology (Mountain View, CA, USA). All solvents were HPLC-MS grade and obtained from Merck (Darmstadt, Germany). Ultra-purified water used in this work was produced with a Milli-Q system (18.2 MΩ·cm−1, Millipore,

BDE-47 exposure facilitated the growth of white adipose tissue in HFD treated mice

Male C57BL/6J mice were exposed to BDE-47 weekly and fed with LFD or HFD for 15 weeks as illustrated in Fig. 1A. After 15 weeks of exposure, the weights of mice bodies and livers were significantly increased by BDE-47 exposure together with HFD intervention (data not shown) as our previously reported (Yang et al., 2019). Interestingly, no obvious differences in the weight of WAT were detected between LFD fed mice from the BDE-47 exposure group and those from the control group (Fig. 1B).

Discussion

Toxicity of environmental pollutants on biological systems usually involves multiple cellular interactions and complex networks among genes, proteins, lipids, and metabolites. Comprehensive integration of targeted metabolite analysis and lipidomics with gene function analysis is crucial for in-depth analyses of the toxicity of environmental pollutants. In this study, we report the link between BDE-47-induced obesity and lipid metabolism dysfunction in mouse WAT, with combined analyses of gene

CRediT authorship contribution statement

Chunxue Yang: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft. Juntong Wei: Methodology, Writing – review & editing, Funding acquisition. Guodong Cao: Methodology. Zongwei Cai: Writing – review & editing, Supervision, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The work was supported by the grants from the National Key Research and Development Program of China (2018YFA0901104), National Natural Science Foundation of China (22036001) and Postdoctoral Research Foundation of China (2021M690785). Dr. Simon Wang at the Language Centre, Hong Kong Baptist University, has helped improve the linguistic presentation of the manuscript.

References (61)

  • E.D. Rosen et al.

    What we talk about when we talk about fat

    Cell

    (2014)
  • J.H. Stern et al.

    Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk

    Cell Metab.

    (2016)
  • K. Sun et al.

    Fibrosis and adipose tissue dysfunction

    Cell Metab.

    (2013)
  • L.-M.L. Toms et al.

    Polybrominated diphenyl ethers (pbdes) in human milk from Australia

    Chemosphere

    (2007)
  • J. Wang et al.

    Legacy and novel brominated flame retardants in indoor dust from Beijing, China: occurrence, human exposure assessment and evidence for pbdes replacement

    Sci. Total Environ.

    (2018)
  • E. Warensjö et al.

    Fatty acid composition and estimated desaturase activities are associated with obesity and lifestyle variables in men and women

    Nutr. Metab. Cardiovasc. Dis.

    (2006)
  • J. Wei et al.

    Metabolomics and lipidomics study unveils the impact of polybrominated diphenyl ether-47 on breast cancer mice

    J. Hazard. Mater.

    (2020)
  • J. Wei et al.

    Derivatization strategy combined with parallel reaction monitoring for the characterization of short-chain fatty acids and their hydroxylated derivatives in mouse

    Anal. Chim. Acta

    (2020)
  • J. Wei et al.

    Derivatization strategy for semi-quantitative analysis of medium-and long-chain fatty acids using multiple reaction monitoring

    Talanta

    (2021)
  • M.R. Wenk

    Lipidomics: new tools and applications

    Cell

    (2010)
  • K.-L. Wong et al.

    Palmitic acid-induced lipotoxicity and protection by (+)-catechin in rat cortical astrocytes

    Pharmacol. Rep.

    (2014)
  • C. Yang et al.

    Persistent organic pollutants as risk factors for obesity and diabetes

    Curr. Diabetes Rep.

    (2017)
  • C. Yang et al.

    The brominated flame retardant bde 47 upregulates purine metabolism and mitochondrial respiration to promote adipocyte differentiation

    Sci. Total Environ.

    (2018)
  • C. Yang et al.

    Chronic exposure to tetrabromodiphenyl ether (bde-47) aggravates hepatic steatosis and liver fibrosis in diet-induced obese mice

    J. Hazard. Mater.

    (2019)
  • M. Yu et al.

    Bioaccumulation and trophic transfer of polybrominated diphenyl ethers (pbdes) in biota from the Pearl River Estuary, south China

    Environ. Int.

    (2009)
  • X. Zhao et al.

    Polybrominated diphenyl ethers in serum from residents living in a brominated flame retardant production area: occurrence, influencing factors, and relationships with thyroid and liver function

    Environ. Pollut.

    (2021)
  • G. Abbasi et al.

    Global historical stocks and emissions of pbdes

    Environ. Sci. Technol.

    (2019)
  • K. Aquilano et al.

    Glutathione: new roles in redox signaling for an old antioxidant

    Front. Pharmacol.

    (2014)
  • Y. Bai et al.

    Macrophage recruitment in obese adipose tissue

    Obes. Rev.

    (2015)
  • M. Blüher

    Obesity: global epidemiology and pathogenesis

    Nat. Rev. Endocrinol.

    (2019)
  • Cited by (22)

    View all citing articles on Scopus
    View full text