Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite. (January 2019)

• Record Type: Journal Article
• Authors: Skledar, Darja Gramec; Carino, Adriana; Trontelj, Jurij; Troberg, Johanna; Distrutti, Eleonora; Marchianò, Silvia; Tomašič, Tihomir; Zega, Anamarija; Finel, Moshe; Fiorucci, Stefano; Mašič, Lucija Peterlin
• Is Part Of: Chemosphere. Volume 215(2019)
• Page Start: 870
• Page End: 880
• Publication Date: 2019-01
• Subjects: Bisphenol AF -- Bisphenol AF glucuronide -- Glucuronidation -- Endocrine activities -- Lipid accumulation; BPA bisphenol A -- BPAF bisphenol AF -- BPAF-G bisphenol AF glucuronide -- BPS bisphenol S -- CDCA chenodeoxycholic acid -- DIM differentiation mix (DMEM, 10% fetal calf serum, 517 μM 3-isobutyl-1-methylxanthine, 1 μM dexamethasone, 172 nM insulin) -- DMEM Dulbecco's modified Eagle's medium -- E2 17-β-estradiol -- ER estrogen receptor -- FXR farnesoid receptor -- HIM human intestine microsomes -- HLM human liver microsomes -- NADPH β-nicotinamide adenine dinucleotide phosphate -- PBS phosphate-buffered saline -- PPAR peroxisome proliferator-activated receptor -- PXR pregnane X receptor -- T3 triiodothyronine -- UDPGA uridine 5'diphosphoglucuronic acid -- UGT 5′-diphospho-glucuronosyltransferase; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2018.10.129
• Languages: English
• ISSNs: 0045-6535

Abstract

Abstract: Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF-glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis. Also, as metabolites can have different biological activities, the effects of BPAF-G on other nuclear receptors were evaluated. First, in-vitro BPAF glucuronidation was investigated using recombinant human enzymes. Specific reporter-gene assays were used to determine BPAF and BPAF-G effects on estrogen, androgen, glucocorticoid, and thyroid receptor pathways, and on PXR, FXR, and PPARγ pathways. Their effects on lipid accumulation and differentiation were determined in murine 3T3L1 preadipocytes using Nile Red, with mRNA expression analysis of the adipogenic markers adiponectin, Fabp4, Cebpα, and PPARγ. BPAF showed strong agonistic activity for hERα and moderate antagonistic activities for androgen and thyroid receptors, and for PXR. BPAF-G was antagonistic for PXR and PPARγ. BPAF (0.1 μM) and BPAF-G (1.0 μM) induced lipid accumulation and increased expression of key adipogenic markers in murine preadipocytes. BPAF-G is therefore not an inactive metabolite of BPAF. Further toxicological and epidemiological investigations of BPAF effects on human health are warranted, to provide better understanding of the metabolic end-elimination of BPAF. Highlights: Influence of metabolism on BPAF endocrine activity and adipogenesis was studied. BPAF is agonist on estrogen and antagonist on androgen, thyroid and PXR receptors. BPAF glucuronide induced lipid accumulation and expression of adipogenic markers. Glucuronidation of BPAF results in formation of biologically active metabolite. Understanding metabolism of BPAF is important for risk assessment of BPAF.