Obesity III: Obesogen assays: Limitations, strengths, and new directions

Kassotis, Christopher D.; Saal, Frederick S. vom; Babin, Pierre; Lagadic‐Gossmann, Dominique; Mentec, Hélène Le; Blumberg, Bruce; Mohajer, Nicole; Legrand, Antoine; Kos, Vesna Munić; Martin-Chouly, Corinne; Podechard, Normand; Langouët, Sophie; Touma, Charbel; Barouki, Robert; Kim, Min Ji; Audouze, Karine; Choudhury, Mahua; Shree, Nitya; Bansal, Amita; Howard, Sarah; Heindel, Jerrold J.

doi:10.1016/j.bcp.2022.115014

Cited by 20 publications

(17 citation statements)

References 278 publications

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“…MSCs have been widely used to study the obesogenic properties of environmental chemicals ( 19 , 20 , 31 , 32 ). We tested the potential obesogenic properties of 2,4-DTBP and 2,6-DTBP using a human MSC adipogenesis assay.…”

Section: Resultsmentioning

confidence: 99%

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

et al. 2023

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2,4-di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. Here we asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell (MSC) adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor γ (PPARγ)-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARγ/RXRα heterodimer by activating RXRα but not directly binding to PPARγ. We confirmed that 2,4-DTBP directly bound to RXRα by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRα. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXRs. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition. Structure-activity studies such as the present one could help guide the rational development of safer antioxidants that do not interact with important nuclear receptors having broad effects on human development and physiology.

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Section: Resultsmentioning

confidence: 99%

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

et al. 2023

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“…MSCs have been widely used to study the obesogenic properties of environmental chemicals 19, 20, 29, 30 . Here, we tested the potential obesogenic properties of 2,4-DTBP and 2,6-DTBP using a human MSC adipogenesis assay.…”

Section: Resultsmentioning

confidence: 99%

“…We further found that 2,4-DTBP can activate the PPARγ-RXRα heterodimer – the so-called “master regulator” of adipogenesis 31 . Activation of PPARγ is a well-established predictor of adipogenic activity, in vivo , and many chemicals have been shown to promote adipogenesis by activating PPARγ (reviewed in 29, 30 ). We used specific PPARγ and RXRα antagonist assays to confirm the requirement for this heterodimer in promoting adipogenesis (Fig.…”

Section: Discussionmentioning

confidence: 99%

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

Ren

Chang

Huang

et al. 2022

Preprint

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2,4-di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. Here we asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell (MSC) adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor γ (PPARγ)-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARγ/RXRα heterodimer by activating RXRα but not directly binding to PPARγ. We confirmed that 2,4-DTBP directly bound to RXRα by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRα. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXR. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition and that structure-activity studies such as the present one could help guide the rational development of safer antioxidants.

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“…Human mesenchymal stem cell and pre-adipocyte models require further validation to improve the translation of this knowledge to human metabolic health. Scientific knowledge can also be improved by combining traditional in vitro models with new assessment techniques such as three-dimensional and co-culture techniques that allow the analysis of environmentally relevant levels of exposure [76].…”

Section: Discussionmentioning

confidence: 99%

The Mixture of Bisphenol-A and Its Substitutes Bisphenol-S and Bisphenol-F Exerts Obesogenic Activity on Human Adipose-Derived Stem Cells

Reina-Pérez

Olivas-Martínez

Mustieles

et al. 2022

Toxics

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Bisphenol A (BPA) and its substitutes, bisphenol F (BPF) and S (BPS), have previously shown in vitro obesogenic activity. This study was designed to investigate their combined effect on the adipogenic differentiation of human adipose-derived stem cells (hASCs). Cells were exposed for 14 days to an equimolar mixture of bisphenols (MIX) (range 10 nM–10 µM). Oil Red staining was used to measure intracellular lipid accumulation, quantitative real-time polymerase chain reaction (qRT-PCR) to study gene expression of adipogenic markers (PPARγ, C/EBPα, LPL, and FABP4), and Western Blot to determine their corresponding proteins. The MIX promoted intracellular lipid accumulation in a dose-dependent manner with a maximal response at 10 µM. Co-incubation with pure antiestrogen (ICI 182,780) inhibited lipid accumulation, suggesting that the effect was mediated by the estrogen receptor. The MIX also significantly altered the expression of PPARγ, C/EBPα, LPL, and FABP4 markers, observing a non-monotonic (U-shaped) dose-response, with maximal gene expression at 10 nM and 10 µM and lesser expression at 1 µM. This pattern was not observed when bisphenols were tested individually. Exposure to MIX (1–10 µM) also increased all encoded proteins except for FABP4, which showed no changes. Evaluation of the combined effect of relevant chemical mixtures is needed rather than single chemical testing.

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Obesity III: Obesogen assays: Limitations, strengths, and new directions

Cited by 20 publications

References 278 publications

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

The Mixture of Bisphenol-A and Its Substitutes Bisphenol-S and Bisphenol-F Exerts Obesogenic Activity on Human Adipose-Derived Stem Cells

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