The increasing use of industrial chemicals has raised concerns regarding exposure to endocrine-disrupting chemicals (EDCs), which interfere with developmental, reproductive and metabolic processes. Of particular concern is their interaction with adipose tissue, a vital component of the endocrine system regulating metabolic and hormonal functions. The SGBS (Simpson Golabi Behmel Syndrome) cell line, a well-established human-relevant model for adipocyte research, closely mimics native adipocytes' properties. It responds to hormonal stimuli, undergoes adipogenesis and has been successfully used to study the impact of EDCs on adipose biology. In this study, we screened human exposure-relevant doses of various EDCs on the SGBS cell line to investigate their effects on viability, lipid accumulation and adipogenesis-related protein expression. Submicromolar doses were generally well tolerated; however, at higher doses, EDCs compromised cell viability, with cadmium chloride (CdCl2) showing the most pronounced effects. Intracellular lipid levels remained unaffected by EDCs, except for tributyltin (TBT), used as a positive control, which induced a significant increase. Analysis of adipogenesis-related protein expression revealed several effects, including downregulation of fatty acid-binding protein 4 (FABP4) by dibutyl phthalate, upregulation by CdCl2 and downregulation of perilipin 1 and FABP4 by perfluorooctanoic acid. Additionally, TBT induced dose-dependent upregulation of C/EBPα, perilipin 1 and FABP4 protein expression. These findings underscore the importance of employing appropriate models to study EDC-adipocyte interactions. Conclusions from this research could guide strategies to reduce the negative impacts of EDC exposure on adipose tissue.

Department of Internal Medicine and Cardiology University Hospital Brno Brno Czech Republic

Department of Physical Activities and Health Sciences Faculty of Sports Studies Masaryk University Brno Czech Republic

Division of Pediatric Endocrinology and Diabetes Department of Pediatrics and Adolescent Medicine University of Ulm Ulm Germany

RECETOX Faculty of Science Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Attia, S. M., Das, S. C., Varadharajan, K., & Al‐Naemi, H. A. (2022). White adipose tissue as a target for cadmium toxicity. Frontiers in Pharmacology, 13(October), 1–9. https://doi.org/10.3389/fphar.2022.1010817

Baker, A. H., Watt, J., Huang, C. K., Gerstenfeld, L. C., & Schlezinger, J. J. (2015). Tributyltin engages multiple nuclear receptor pathways and suppresses osteogenesis in bone marrow multipotent stromal cells. Chemical Research in Toxicology, 28(6), 1156–1166. https://doi.org/10.1021/tx500433r

Biemann, R., Navarrete Santos, A., Navarrete Santos, A., Riemann, D., Knelangen, J., Blüher, M., Koch, H., & Fischer, B. (2012). Endocrine disrupting chemicals affect the adipogenic differentiation of mesenchymal stem cells in distinct ontogenetic windows. Biochemical and Biophysical Research Communications, 417(2), 747–752. https://doi.org/10.1016/j.bbrc.2011.12.028

Binó, L., Procházková, J., Radaszkiewicz, K. A., Kucera, J., Kudová, J., Pacherník, J., & Kuala, L. (2017). Hypoxia favors myosin heavy chain beta gene expression in an Hif‐1alpha‐dependent manner. Oncotarget, 8(48), 83684–83697. https://doi.org/10.18632/oncotarget.19016

de Cock, M., & van de Bor, M. (2014). Obesogenic effects of endocrine disruptors, what do we know from animal and human studies? Environment International, 70, 15–24. https://doi.org/10.1016/j.envint.2014.04.022

de Coster, S., & van Larebeke, N. (2012). Endocrine‐disrupting chemicals: Associated disorders and mechanisms of action. Journal of Environmental and Public Health, 2012, 1–52. https://doi.org/10.1155/2012/713696

de Filippis, E., Li, T., & Rosen, E. D. (2018). Exposure of adipocytes to bisphenol‐A in vitro interferes with insulin action without enhancing adipogenesis. PLoS ONE, 13(8), 1–14. https://doi.org/10.1371/journal.pone.0201122

Desgrouas, C., Thalheim, T., Cerino, M., Badens, C., & Bonello‐Palot, N. (2024). Perilipin 1: A systematic review on its functions on lipid metabolism and atherosclerosis in mice and humans. Cardiovascular Research, 120(3), 237–248. https://doi.org/10.1093/cvr/cvae005

Encarnação, T., Pais, A. A. C. C., Campos, M. G., & Burrows, H. D. (2019). Endocrine disrupting chemicals: Impact on human health, wildlife and the environment. Science Progress, 102(1), 3–42. https://doi.org/10.1177/0036850419826802

Ernst, J., Grabiec, U., Falk, K., Dehghani, F., & Schaedlich, K. (2020). The endocrine disruptor DEHP and the ECS: Analysis of a possible crosstalk. Endocrine Connections, 9(2), 101–110. https://doi.org/10.1530/EC-19-0548

Fischer‐Posovszky, P., Newell, F. S., Wabitsch, M., & Tornqvist, H. E. (2008). Human SGBS cells—A unique tool for studies of human fat cell biology. Obesity Facts, 1(4), 184–189. https://doi.org/10.1159/000145784

Furuhashi, M., Saitoh, S., Shimamoto, K., & Miura, T. (2014). Fatty acid‐binding protein 4 (FABP4): Pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. Clinical Medicine Insights: Cardiology, 8(Suppl 3), 23–33. https://doi.org/10.4137/CMC.S17067

Gasser, M., Lenglet, S., Bararpour, N., Sajic, T., Wiskott, K., Augsburger, M., Fracasso, T., Gilardi, F., & Thomas, A. (2022). Cadmium acute exposure induces metabolic and transcriptomic perturbations in human mature adipocytes. Toxicology, 470(October 2021), 153153. https://doi.org/10.1016/j.tox.2022.153153

Grün, F., Watanabe, H., Zamanian, Z., Maeda, L., Arima, K., Cubacha, R., Gardiner, D. M., Kanno, J., Iguchi, T., & Blumberg, B. (2006). Endocrine‐disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Molecular Endocrinology, 20(9), 2141–2155. https://doi.org/10.1210/me.2005-0367

Heindel, J. J., Blumberg, B., Cave, M., Machtinger, R., Mantovani, A., Mendez, M. A., Nadal, A., Palanza, P., Panzica, G., Sargis, R., Vandenberg, L. N., & vom Saal, F. (2017). Metabolism disrupting chemicals and metabolic disorders. Reproductive Toxicology, 68, 3–33. https://doi.org/10.1016/j.reprotox.2016.10.001

Heindel, J. J., Newbold, R., & Schug, T. T. (2015). Endocrine disruptors and obesity. Nature Reviews. Endocrinology, 11(11), 653–661. https://doi.org/10.1038/nrendo.2015.163

Inoue, K., Kawaguchi, M., Yamanaka, R., Higuchi, T., Ito, R., Saito, K., & Nakazawa, H. (2005). Evaluation and analysis of exposure levels of di(2‐ethylhexyl) phthalate from blood bags. Clinica Chimica Acta, 358(1–2), 159–166. https://doi.org/10.1016/j.cccn.2005.02.019

Janesick, A. S., & Blumberg, B. (2016). Obesogens: An emerging threat to public health. American Journal of Obstetrics and Gynecology, 214(5), 559–565. https://doi.org/10.1016/j.ajog.2016.01.182

Li, H., Li, J., Qu, Z., Qian, H., Zhang, J., Wang, H., Xu, X., & Liu, S. (2020). Intrauterine exposure to low‐dose DBP in the mice induces obesity in offspring via suppression of UCP1 mediated ER stress. Scientific Reports, 10(1), 1–12. https://doi.org/10.1038/s41598-020-73477-3

Li, X., Ycaza, J., & Blumberg, B. (2011). The environmental obesogen tributyltin chloride acts via peroxisome proliferator activated receptor gamma to induce adipogenesis in murine 3T3‐L1 preadipocytes. Journal of Steroid Biochemistry and Molecular Biology, 127(1–2), 9–15. https://doi.org/10.1016/j.jsbmb.2011.03.012

Lutfi, E., Riera‐Heredia, N., Córdoba, M., Porte, C., Gutiérrez, J., Capilla, E., & Navarro, I. (2017). Tributyltin and triphenyltin exposure promotes in vitro adipogenic differentiation but alters the adipocyte phenotype in rainbow trout. Aquatic Toxicology, 188(May), 148–158. https://doi.org/10.1016/j.aquatox.2017.05.001

Modaresi, S. M. S., Wei, W., Emily, M., DaSilva, N. A., & Slitt, A. L. (2022). Per‐ and polyfluoroalkyl substances (PFAS) augment adipogenesis and shift the proteome in murine 3T3‐L1 adipocytes. Toxicology, 465(October 2021), 153044. https://doi.org/10.1016/j.tox.2021.153044

Oliviero, F., Marmugi, A., Viguié, C., Gayrard, V., Picard‐Hagen, N., & Mselli‐Lakhal, L. (2022). Are BPA substitutes as obesogenic as BPA? International Journal of Molecular Sciences, 23(8), 4238. https://doi.org/10.3390/ijms23084238

Ouadah‐Boussouf, N., & Babin, P. J. (2016). Pharmacological evaluation of the mechanisms involved in increased adiposity in zebrafish triggered by the environmental contaminant tributyltin. Toxicology and Applied Pharmacology, 294, 32–42. https://doi.org/10.1016/j.taap.2016.01.014

Ramskov Tetzlaff, C. N., Svingen, T., Vinggaard, A. M., Rosenmai, A. K., & Taxvig, C. (2020). Bisphenols B, E, F, and S and 4‐cumylphenol induce lipid accumulation in mouse adipocytes similarly to bisphenol A. Environmental Toxicology, 35, 543–552. https://doi.org/10.1002/tox.22889

Reckziegel, P., Petrovic, N., Cannon, B., & Nedergaard, J. (2024). Perfluorooctanoate (PFOA) cell‐autonomously promotes thermogenic and adipogenic differentiation of brown and white adipocytes. Ecotoxicology and Environmental Safety, 271(September 2023), 115955. https://doi.org/10.1016/j.ecoenv.2024.115955

Rosen, E. D., Hsu, C., Wang, X., Sakai, S., Freeman, M. W., Gonzalez, F. J., & Spiegelman, B. M. (2002). C/EBPα induces adipogenesis through PPARγ: A unified pathway. Genes & Development, 16(1), 22–26. https://doi.org/10.1101/gad.948702

Schaedlich, K., Gebauer, S., Hunger, L., Beier, L. S., Koch, H. M., Wabitsch, M., Fischer, B., & Ernst, J. (2018). DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS‐adipocytes. Scientific Reports, 8(1), 1–14. https://doi.org/10.1038/s41598-018-21800-4

Schaffert, A., Karkossa, I., Ueberham, E., Schlichting, R., Walter, K., Arnold, J., Blüher, M., Heiker, J. T., Lehmann, J., Wabitsch, M., Escher, B. I., von Bergen, M., & Schubert, K. (2022). Di‐(2‐ethylhexyl) phthalate substitutes accelerate human adipogenesis through PPARγ activation and cause oxidative stress and impaired metabolic homeostasis in mature adipocytes. Environment International, 164(April), 107279. https://doi.org/10.1016/j.envint.2022.107279

Schaffert, A., Krieg, L., Weiner, J., Schlichting, R., Ueberham, E., Karkossa, I., Bauer, M., Landgraf, K., Junge, K. M., Wabitsch, M., Lehmann, J., Escher, B. I., Zenclussen, A. C., Körner, A., Blüher, M., Heiker, J. T., von Bergen, M., & Schubert, K. (2021). Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environment International, 156, 106730. https://doi.org/10.1016/j.envint.2021.106730

Singh, M., Crosthwait, J., Sorisky, A., & Atlas, E. (2024). Tetra methyl bisphenol F: Another potential obesogen. International Journal of Obesity, 48, 923–933. https://doi.org/10.1038/s41366-024-01496-5

Tews, D., Brenner, R. E., Siebert, R., Debatin, K. M., Fischer‐Posovszky, P., & Wabitsch, M. (2022). 20 years with SGBS cells—A versatile in vitro model of human adipocyte biology. International Journal of Obesity, 46(11), 1939–1947. https://doi.org/10.1038/s41366-022-01199-9

Valentino, R., D'Esposito, V., Passaretti, F., Liotti, A., Cabaro, S., Longo, M., Perruolo, G., Oriente, F., Beguinot, F., & Formisano, P. (2013). Bisphenol‐A impairs insulin action and up‐regulates inflammatory pathways in human subcutaneous adipocytes and 3T3‐L1 cells. PLoS ONE, 8(12), 1–10. https://doi.org/10.1371/journal.pone.0082099

van den Dungen, M. W., Murk, A. J., Kok, D. E., & Steegenga, W. T. (2017). Persistent organic pollutants alter DNA methylation during human adipocyte differentiation. Toxicology in Vitro, 40, 79–87. https://doi.org/10.1016/j.tiv.2016.12.011

Večeřa, J., Kudová, J., Kučera, J., Kubala, L., & Pacherník, J. (2017). Neural differentiation is inhibited through HIF1 α/β‐catenin signaling in embryoid bodies. Stem Cells International, 2017, 1–12. https://doi.org/10.1155/2017/8715798

Wabitsch, M., Brenner, R. E., Melzner, I., Braun, M., Möller, P., Heinze, E., Debatin, K. M., & Hauner, H. (2001). Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. International Journal of Obesity, 25(1), 8–15. https://doi.org/10.1038/sj.ijo.0801520

Wada, K., Sakamoto, H., Nishikawa, K., Sakuma, S., Nakajima, A., Fujimoto, Y., & Kamisaki, Y. (2007). Life style‐related diseases of the digestive system: Endocrine disruptors stimulate lipid accumulation in target cells related to metabolic syndrome. Journal of Pharmacological Sciences, 105(2), 133–137. https://doi.org/10.1254/jphs.FM0070034

Xu, J., Shimpi, P., Armstrong, L., Salter, D., & Slitt, A. L. (2016). PFOS induces adipogenesis and glucose uptake in association with activation of Nrf2 signaling pathway. Toxicology and Applied Pharmacology, 290(1), 21–30. https://doi.org/10.1016/j.taap.2015.11.002