Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jul;120(7):984-9.
doi: 10.1289/ehp.1205063. Epub 2012 May 25.

Bisphenol A diglycidyl ether induces adipogenic differentiation of multipotent stromal stem cells through a peroxisome proliferator-activated receptor gamma-independent mechanism

Raquel Chamorro-García  1 , Séverine Kirchner, Xia Li, Amanda Janesick, Stephanie C Casey, Connie Chow, Bruce Blumberg
Affiliations

Bisphenol A diglycidyl ether induces adipogenic differentiation of multipotent stromal stem cells through a peroxisome proliferator-activated receptor gamma-independent mechanism

Raquel Chamorro-García et al. Environ Health Perspect. 2012 Jul.

Abstract

Background: Bisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE), used in manufacturing coatings and resins, leach from packaging materials into food. Numerous studies suggested that BPA and BADGE may have adverse effects on human health, including the possibility that exposure to such chemicals can be superimposed on traditional risk factors to initiate or exacerbate the development of obesity. BPA is a suspected obesogen, whereas BADGE, described as a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, could reduce weight gain.

Objectives: We sought to test the adipogenic effects of BADGE in a biologically relevant cell culture model.

Methods: We used multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of BADGE and BPA and evaluated their effects on adipogenesis, osteogenesis, gene expression, and nuclear receptor activation.

Discussion: BADGE induced adipogenesis in human and mouse MSCs, as well as in mouse 3T3-L1 preadipocytes. In contrast, BPA failed to promote adipogenesis in MSCs, but induced adipogenesis in 3T3-L1 cells. BADGE exposure elicited an adipogenic gene expression profile, and its ability to induce adipogenesis and the expression of adipogenic genes was not blocked by known PPARγ antagonists. Neither BADGE nor BPA activated or antagonized retinoid "X" receptor (RXR) or PPARγ in transient transfection assays.

Conclusions: BADGE can induce adipogenic differentiation in both MSCs and in preadipocytes at low nanomolar concentrations comparable to those that have been observed in limited human biomonitoring. BADGE probably acts through a mechanism that is downstream of, or parallel to, PPARγ.

PubMed Disclaimer

Conflict of interest statement

B.B. is a named inventor on U.S. patents 5,861,274, 6,200,802, 6,815,168, and 7,250,273 related to PPARγ. The other authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Dose response of MSCs adipogenic capacities to in vitro exposure to BADGE and BPA. Adipogenesis was induced in hMSCs (A) and mMSCs (B) by the addition of an adipogenic cocktail for 14 days in the absence (DMSO) or presence of ROSI 500 nM or increasing doses of BADGE and BPA. All data are expressed as mean ± SE lipid accumulation in six replicates. *p < 0.05, **p < 0.01, and #p < 0.001 relative to vehicle (DMSO) controls.
Figure 2
Figure 2
In vitro effect of BADGE exposure on the adipogenic capacities of hMSCs and mMSCs. Lipid accumulation in hMSCs (A) and mMSCs (B) (left). Adipogenesis was induced in MSCs by the addition of an adipogenic cocktail for 14 days with DMSO, 500 nM ROSI, 100 nM BADGE, or 100 nM BPA. Gene expression profile in hMSCs and mMSCs was assayed by QPCR (right) [early adipogenesis markers: PPARγ2, Pref-1, and FABP4; late adipogenesis markers: LEP, LPL, and ADIPOQ]. Expression was normalized to β-actin. (C) FABP4 protein levels were assayed by flow cytometry. Median fluorescence intensities (MFI) are represented relative to vehicle (DMSO) controls. ADIPOQ, adiponectin. All data are expressed as mean fold change ± SE in six replicates. *p < 0.05, **p < 0.01, and #p < 0.001 relative to vehicle (DMSO) controls.
Figure 3
Figure 3
Neither BADGE nor BPA affects PPARγ or RXR activity in transient transfection assays. The ability of a graded dose series of BADGE or BPA to activate or antagonize GAL4-hPPARγ and GAL-hRXRα was tested in transiently transfected COS7 cells. (A,B) Activation assays: BADGE and BPA (10–10 M through 10–4 M) were tested with 10–4 M producing noticeable cytotoxicity as judged by β-galactosidase activity. The control compounds ROSI (PPARγ agonist) and LG-268 (RXR agonist) were also tested (10–10 through 10–5 M). Neither BADGE nor BPA activated PPARγ or RXR. (C,D) Antagonism assays: BADGE, BPA, GW9662 (PPARγ antagonist), and HX-531 (RXR antagonist) were tested (10–10 through 10–5 M) against 10–7 M ROSI (PPARγ; C) or 10–7 M LG-268 (RXRα; D). Although GW9662 effectively antagonized PPARγ activity, BADGE and BPA did not. HX-531 antagonized RXRα at 10–5 M, whereas BADGE and BPA were inactive. Data are presented as fold induction over vehicle (0.1% DMSO) controls for activation assays or as fold reduction over 10–7 M ROSI or 10–7 M LG-268 for antagonism assays.
Figure 4
Figure 4
Effect of the PPARγ antagonist T0070907 in BADGE- or BPA-induced adipogenic abilities of MSCs. Adipogenesis was induced in hMSCs (A) or mMSCs (B) by the addition of an adipogenic cocktail for 14 days with DMSO, 500 nM ROSI, 100 nM BADGE, or 100 nM BPA in the presence of DMSO or 100 nM T0070907 (PPARγ antagonist). All data are expressed as mean ± SE lipid accumulation in six replicates. *p < 0.05, and **p < 0.01 relative to vehicle (DMSO) controls.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Triflumizole is an obesogen in mice that acts through peroxisome proliferator activated receptor gamma (PPARγ).
    Li X, Pham HT, Janesick AS, Blumberg B. Li X, et al. Environ Health Perspect. 2012 Dec;120(12):1720-6. doi: 10.1289/ehp.1205383. Epub 2012 Sep 22. Environ Health Perspect. 2012. PMID: 23086663 Free PMC article.
  • Quizalofop-p-Ethyl Induces Adipogenesis in 3T3-L1 Adipocytes.
    Biserni M, Mesnage R, Ferro R, Wozniak E, Xenakis T, Mein CA, Antoniou MN. Biserni M, et al. Toxicol Sci. 2019 Aug 1;170(2):452-461. doi: 10.1093/toxsci/kfz097. Toxicol Sci. 2019. PMID: 31086981 Free PMC article.
  • Current Evidence on Bisphenol A Exposure and the Molecular Mechanism Involved in Related Pathological Conditions.
    Della Rocca Y, Traini EM, Diomede F, Fonticoli L, Trubiani O, Paganelli A, Pizzicannella J, Marconi GD. Della Rocca Y, et al. Pharmaceutics. 2023 Mar 10;15(3):908. doi: 10.3390/pharmaceutics15030908. Pharmaceutics. 2023. PMID: 36986769 Free PMC article. Review.
  • Obesity III: Obesogen assays: Limitations, strengths, and new directions.
    Kassotis CD, Vom Saal FS, Babin PJ, Lagadic-Gossmann D, Le Mentec H, Blumberg B, Mohajer N, Legrand A, Munic Kos V, Martin-Chouly C, Podechard N, Langouët S, Touma C, Barouki R, Kim MJ, Audouze K, Choudhury M, Shree N, Bansal A, Howard S, Heindel JJ. Kassotis CD, et al. Biochem Pharmacol. 2022 May;199:115014. doi: 10.1016/j.bcp.2022.115014. Epub 2022 Apr 5. Biochem Pharmacol. 2022. PMID: 35393121 Free PMC article. Review.
  • Obesity II: Establishing causal links between chemical exposures and obesity.
    Heindel JJ, Howard S, Agay-Shay K, Arrebola JP, Audouze K, Babin PJ, Barouki R, Bansal A, Blanc E, Cave MC, Chatterjee S, Chevalier N, Choudhury M, Collier D, Connolly L, Coumoul X, Garruti G, Gilbertson M, Hoepner LA, Holloway AC, Howell G 3rd, Kassotis CD, Kay MK, Kim MJ, Lagadic-Gossmann D, Langouet S, Legrand A, Li Z, Le Mentec H, Lind L, Monica Lind P, Lustig RH, Martin-Chouly C, Munic Kos V, Podechard N, Roepke TA, Sargis RM, Starling A, Tomlinson CR, Touma C, Vondracek J, Vom Saal F, Blumberg B. Heindel JJ, et al. Biochem Pharmacol. 2022 May;199:115015. doi: 10.1016/j.bcp.2022.115015. Epub 2022 Apr 5. Biochem Pharmacol. 2022. PMID: 35395240 Free PMC article. Review.
See all "Cited by" articles

References

    1. Avram MM, Avram AS, James WD. Subcutaneous fat in normal and diseased states 3. Adipogenesis: from stem cell to fat cell. J Am Acad Dermatol. 2007;56(3):472–492. - PubMed
    1. Biedermann M, Grob K. Food contamination from epoxy resins and organosols used as can coatings: analysis by gradient NPLC. Food Addit Contam. 1998;15(5):609–618. - PubMed
    1. Bishop-Bailey D, Hla T, Warner TD. Bisphenol A diglycidyl ether (BADGE) is a PPARγ agonist in an ECV304 cell line. Br J Pharmacol. 2000;131(4):651–654. - PMC - PubMed
    1. Cabado AG, Aldea S, Porro C, Ojea G, Lago J, Sobrado C, et al. Migration of BADGE (bisphenol A diglycidyl-ether) and BFDGE (bisphenol F diglycidyl-ether) in canned seafood. Food Chem Toxicol. 2008;46(5):1674–1680. - PubMed
    1. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect. 2008;116:39–44. - PMC - PubMed

Publication types

LinkOut - more resources

  NODES
chat 1
twitter 2