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Background Polybrominated diphenyl ethers (PBDEs), a widely utilized class of flame retardants in various commercial products, represent a prominent source of environmental contaminants. PBDEs tend to accumulate in adipose tissue, potentially altering the function of this endocrine organ and increasing risk of insulin resistance. The aim of this study was to compare levels of PBDEs in adipose tissues from two metabolically distinct obese groups; the insulin sensitive (IS) and the insulin resistant (IR). Methods Levels of 28 PBDE congeners were assessed in subcutaneous and omental adipose tissues from 34 obese Qatari individuals (11 IS and 23 IR) using gas chromatography (Trace GC Ultra) coupled to a TSQ Quantum triple Quadrupole mass spectrometer. Correlations of identified PBDEs and mediators of metabolic disease were established and effects of PBDEs treatment on insulin signaling in primary omental preadipocytes were determined. Results Out of 22 detectable PBDEs in subcutaneous and omental adipose tissues, PBDEs 28, 47, 99 and 153 were predominant in omental adipose tissues from obese Qatari subjects. PBDEs 99, 28, and 47 were significantly higher in IR individuals compared to their IS counterparts. Significant positive correlations were identified between PBDEs 28 and 99 in the omental tissues and with fasting insulin levels. When considering PBDEs congeners, penta congeners were also higher in IR compared to IS individuals, while no significant differences were detected in mono, tri, tertra, hexa, hepta and octa congeners between the two studied groups. Treatment of human omental preadipocytes from insulin sensitive individuals with PBDE28 caused inhibition of phosphorylation of GSK3 α/β (Ser21/Ser9), mTOR (Ser2448), p70 S6 kinase (Thr389) and S6 ribosomal protein (Ser235/Ser236) and activation of PTEN (Ser380) phosphorylation, suggesting inhibition of insulin signaling. Conclusion This pilot data suggests that accumulation of specific PBDEs in human adipose tissues is associated with insulin resistance in obese individuals. Further investigation of the functional role of PBDEs in the pathology of insulin resistance should help developing therapeutic strategies targeting obese individuals at higher risk.

Murad Helaleh1, Ilhame Diboun2, Nada Altamimi1, Aishah Latiff1, Mohamed Elrayess1* 1Toxicology and Multipurpose Lab, Anti Doping Laboratory Qatar, Sports City, Doha, Qatar. 2 Department of Economics, Mathematics and Statistics, Birkbeck, University of London, London WC1E 7HX, UK. Corresponding author: melrayess@adlqatar.qaAbstractPolybrominated diphenyl ethers (PBDEs) represent a class of widely utilized flame retardants [1]. With over 200 congeners that vary by the extent of halogenations, various PBDEs can leak freely into the environment [2, 3]. Despite cessation of their manufacturing, concerns of their bioaccumulation remain [4-6] due to their stability in products manufactured before the ban and recycled materials [1]. With their high lipophilicity, PBDEs tend to accumulate in adipose tissue, potentially altering the function of this endocrine organ by increasing lipolysis and decreasing glucose oxidation, causing increased risk of metabolic disease including obesity, insulin resistance and type 2 diabetes [7]. Exposure to PBDE-47, for example, during the early post-natal period was shown to induce disturbance in glucose metabolism causing insulin resistance in susceptible mice [8]. In this study, levels of various PBDEs were assessed in subcutaneous and omental adipose tissues from 33 obese and morbidly obese patients (11 insulin sensitive and 22 insulin resistant) and their correlation with mediators of metabolic disease were established. Our results suggested that out of 22 detectable PBDEs in subcutaneous and omental adipose tissues, PBDE99, 28, 47 and 126 were significantly higher in insulin resistant individuals compared to their insulin sensitive counterparts. When considering PBDEs congeners, penta congeners as a group were also higher in insulin resistant individuals compared to insulin sensitive counterparts, while no significant differences were detected in mono, tri, tertra, hexa, hepta and octa congeners between the two studied groups. This data suggest that accumulation of various PBDEs in human adipose tissues obtained from obese individuals is associated with increased risk of insulin resistance. Further investigation of the functional relevance of these associations is currently underway. This study is partly funded by QNRF's grant number NPRP6-235-1-048. References 1. Birnbaum, L.S. and D.F. Staskal, Brominated flame retardants: cause for concern? Environ Health Perspect, 2004. 112(1): p. 9-17. 2. Chen, D. and R.C. Hale, A global review of polybrominated diphenyl ether flame retardant contamination in birds. Environ Int, 2010. 36(7): p. 800-11. 3. Ernest, S.R., et al., Effects of chronic exposure to an environmentally relevant mixture of brominated flame retardants on the reproductive and thyroid system in adult male rats. Toxicol Sci, 2012. 127(2): p. 496-507. 4. Kelly, B.C., et al., Bioaccumulation behaviour of polybrominated diphenyl ethers (PBDEs) in a Canadian Arctic marine food web. Sci Total Environ, 2008. 401(1-3): p. 60-72. 5. Mercado-Feliciano, M. and R.M. Bigsby, Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands. Environ Health Perspect, 2008. 116(10): p. 1315-21. 6. Sjodin, A., D.G. Patterson, Jr., and A. Bergman, A review on human exposure to brominated flame retardants–particularly polybrominated diphenyl ethers. Environ Int, 2003. 29(6): p. 829-39. 7. Hoppe, A.A. and G.B. Carey, Polybrominated diphenyl ethers as endocrine disruptors of adipocyte metabolism. Obesity (Silver Spring), 2007. 15(12): p. 2942-50. 8. McIntyre, R.L., et al., Polybrominated diphenyl ether congener, BDE-47, impairs insulin sensitivity in mice with liver-specific Pten deficiency. BMC Obes, 2015. 2: p. 3.