Adipogenic Effects and Gene Expression Profiling of Firemaster® 550 Components in Human Primary Preadipocytes

Tung, Emily W. Y.; Peshdary, Vian; Gagné, Rémi; Rowan-Carroll, Andrea; Yauk, Carole L.; Boudreau, Adèle; Atlas, Ella

doi:10.1289/ehp1318

Cited by 30 publications

(15 citation statements)

References 40 publications

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“…Like in 3T3-L1 cells and in mice in vivo, TPhP fails to induce brite adipocyte differentiation in primary human preadipocytes. In accordance with a previous study (Tung et al 2017b), TPhP induced lipid accumulation and expression of white adipocyte genes (i.e. Plin1 and Cidec).…”

Section: Discussionsupporting

confidence: 93%

“…OPEs and their metabolites are ligands for multiple human nuclear receptors (Kojima et al 2013(Kojima et al , 2016. There is strong evidence that TPhP is a peroxisome proliferator-activated receptor γ (PPARγ) ligand and is adipogenic (Belcher et al 2014;Fang et al 2015;Pillai et al 2014;Tung et al 2017aTung et al , 2017b. TPhP induced lipid accumulation and perilipin (lipid droplet marker) protein expression in mouse BMS2 cells and increased adipocyte protein 2 (aP2) mRNA expression in mouse 3T3-L1 adipocytes (Pillai et al 2014;Tung et al 2017a).…”

Section: Introductionmentioning

confidence: 99%

“…TPhP induced lipid accumulation and perilipin (lipid droplet marker) protein expression in mouse BMS2 cells and increased adipocyte protein 2 (aP2) mRNA expression in mouse 3T3-L1 adipocytes (Pillai et al 2014;Tung et al 2017a). TPhP induced lipid accumulation and increased FABP4 and LPL mRNA expression in human preadipocytes (Tung et al 2017b).…”

Section: Introductionmentioning

confidence: 99%

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Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Kim

Rabhi

Blum

et al. 2019

Preprint

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Background: Triphenyl phosphate (TPhP) is an environmental PPARγ ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression.Objectives: First, we tested whether TPhP also fails to induce brite adipogenesis in vivo, in human primary preadipocytes and in 3T3 L1 cells. Second, we tested the hypothesis that TPhP is a selective PPARγ modulator that is unable to protect PPARγ from phosphorylation at serine 273.Methods: C57BL/6J male mice were fed either a low or very high fat diet for 13 weeks. From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Mature adipocytes were isolated from inguinal adipose tissue to assess adipocyte gene expression. Adipocyte genotype and phenotype were assessed in human primary preadipocytes differentiated in the presence of Rosi, or TPhP. Adipocyte gene and protein expression were determined in 3T3 L1 cells differentiated in the presence of Rosi or TPhP. Swiss 3T3 cell lines expressing wild-type PPARγ2 or PPARγ2 with alanine substitute for serine at position 273 were used to determine effects of PPARγ phosphorylation on Rosiand TPhP-induced gene expression.Results: Compared to Rosi, TPhP did not induce browning of mature adipocytes. TPhP also did not induce expression of brite adipocyte genes, mitochondrial biogenesis or cellular respiration in primary human adipocytes. Rosi and TPhP induced distinct proteomic and phosphoproteomic profiles; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins. Furthermore, TPhP maintained phosphorylation of PPARγ at ser273. Upon inhibition of phosphorylation at ser273, TPhP was able to induce brite adipocyte genes.Discussion: Here, we show that TPhP acts via a novel mechanism of action. TPhP disrupts brite adipocyte differentiation by failing to protect PPARγ from phosphorylation at ser273, in contrast to the therapeutic PPARγ ligand Rosi.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Kim

Rabhi

Blum

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Perhaps the strongest argument raised against the transmission of epigenetic marks such as DNA methylation is that genome-wide epigenetic reprogramming in mammalian germline cells should erase epimutations from the preceding T A B L E 1 List of known obesogens and potential obesogens with selected end-points and references. The reader should also consult references in previous review articles 46,121 Major use category 131,132 Triphenyl Phosphate + + Lipid accumulation; increased body-weight and fat mass in mice 134,135 FM-550 + + Lipid accumulation; weight gain 134,135,137,138 Pesticide Chlorpyrifos + Weight gain and hyperinsulinemia in rats 141,142 Quinoxyfen + Induce adipogenesis and adipogenic gene expression in 3T3-L1 cells 90 Forchlorfenuron + Induce adipogenesis and adipogenic gene expression in 3T3-L1 cells 90 Flusilazole + Induce adipogenesis and adipogenic gene expression in 3T3-L1 cells generation. 111,112 Some investigators report stable transgenerational changes in DNA methylation 110,114,115 ; others found that the same chemicals induced epimutations and alterations in gene expression in the F1 generation, but that these were not conserved in F2 prospermatogonia.…”

Section: Obesogens Can Be Heritablementioning

confidence: 99%

Transgenerational effects of obesogens

Lee

Blumberg

2019

Basic Clin Pharma Tox

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Obesity and associated disorders are now a global pandemic. The prevailing clinical model for obesity is overconsumption of calorie‐dense food and diminished physical activity (the calories in—calories out model). However, this explanation does not account for numerous recent research findings demonstrating that a variety of environmental factors can be superimposed on diet and exercise to influence the development of obesity. The environmental obesogen model proposes that exposure to chemical obesogens during in utero and/or early life can strongly influence later predisposition to obesity. Obesogens are chemicals that inappropriately stimulate adipogenesis and fat storage, in vivo either directly or indirectly. Numerous obesogens have been identified in recent years and some of these elicit transgenerational effects on obesity as well as a variety of health end‐points after exposure of pregnant F0 females. Prenatal exposure to environmental obesogens can produce lasting effects on the exposed animals and their offspring to at least the F4 generation. Recent results show that some of these transgenerational effects of obesogen exposure can be carried across the generations via alterations in chromatin structure and accessibility. That some chemicals can have permanent effects on the offspring of exposed animals suggests increased caution in the debate about whether and to what extent exposure to endocrine‐disrupting chemicals and obesogens should be regulated.

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“…We also identified mechanistic evidence pointing towards an effect of TPhP and TBBPA on metabolic disorders but only very few studies addressed these adverse effects in animal models or in humans. For example, several in vitro studies reported adipogenesis and/or lipid accumulation and two studies showed increase in body weight associated with TPhP exposure in humans and rodents, and with TBBPA exposure in fish [6,35,52,55,56,65,66,70]. In addition, activation of PPARγ (the MIE of AOP 72 that leads to obesity) by TPhP and TBBPA has been reported in many in vitro studies, two ToxCast assays and in zebrafish, with effective doses below 1 µM for TBBPA only (for example: [17,54,55]).…”

Section: Possible Aos Of Cat I Frs Predicted From Aop Searchmentioning

confidence: 99%

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

2019

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Background: Flame retardants (FRs) are used in most consumer products and textiles to comply with current flammability standards. After the restriction of polybrominated diphenyl ethers, a large number of chemically diverse replacement FRs are increasingly used, but the risk they represent is not yet properly evaluated and their toxicity pathways are still poorly understood. Approach:We collected in vivo toxicological information on 62 (including 52 non-regulated) FRs and established five prioritization categories (Cat I to V) based on data availability and toxicological concern. We then considered available in vitro toxicological data from ToxCast, as a complement to in vivo information. By combining these information sources, we then explored relevant toxicity mechanisms for nine selected FRs (Cat I) using the AOP (Adverse Outcome Pathway) framework. Results:For 20 FRs (Cat V), toxicological data on mammals were absent. Data available were scarce for another 22 FRs, of which 14 FRs (Cat II) may be of toxicological concern. We found substantial information for only ten replacement FRs, of which nine (Cat I) present some toxicological concern: tris-2-chloroethyl phosphate (TCEP), tris(1,3dichloropropyl)phosphate (TDCIPP), triphenyl phosphate (TPhP), tricresyl phosphate (TMPP), tetrabromobisphenol A (TBBPA), tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), tris(1-chloro-2-propyl) phosphate (TCIPP), 2-ethylhexyl diphenyl phosphate (EHDPP). ToxCast results confirmed in vivo based categorization for several FRs and identified potential molecular targets. For the nine Cat I FRs, we identified several molecular targets, health outcomes and some potential AOPs. However, the complete toxicity pathways leading from molecular targets to adverse health outcomes are still unknown, with the exception of TBBPA-induced neurotoxicity. Conclusions:The approach presented in this study was particularly useful for the categorization of a large group of replacement FRs with relatively low data availability. We highlight priority compounds that critically need more toxicological studies or FRs for which regulatory measures could be envisaged. Our research also suggests that high toxicity indicated by ToxCast is particularly relevant for predicting higher hazard in vivo. Finally, we indicate several gaps and directions for future research, such as molecular targets that could be tested in vitro and health outcomes for cohort studies. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Adipogenic Effects and Gene Expression Profiling of Firemaster® 550 Components in Human Primary Preadipocytes

Cited by 30 publications

References 40 publications

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Transgenerational effects of obesogens

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

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