Thyroid receptor antagonism as a contributory mechanism for adipogenesis induced by environmental mixtures in 3T3-L1 cells

Kassotis, Christopher D.; Kollitz, Erin M.; Hoffman, Kate; Sosa, Julie Ann; Stapleton, Heather M.

doi:10.1016/j.scitotenv.2019.02.273

Cited by 21 publications

(12 citation statements)

References 78 publications

(112 reference statements)

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“…This could be one possible explanation for why the concentrations of OPEs designated as inactive in Tox21 screening assays had statistically significant associations with PPARc antagonism in dust samples. That result could also be partly explained by the fact that the inactive-designated OPEs are sometimes correlated with other unmeasured FRs or phthalate plasticizers (Bi et al 2018;Castorina et al 2017;Kassotis et al 2019;Kollitz et al 2018) or could be influenced by the small error that could be introduced from using designations based on a PPARc antagonism assay with a different reporter gene (beta-lactamase) and human cell line tissue type (embryonic kidney) than our dust assays. However, another previous study that measured PPARc antagonism of OPEs using the same luciferase reporter gene assays and human osteosarcoma cell lines as our study was consistent in classifying the four Tox21-inactive chemicals found in our samples at the highest concentrations as inactive (Suzuki et al 2013).…”

Section: Methods Evaluation Of Potency-weighted Concentrations Of Chemical Classesmentioning

confidence: 98%

“…Few studies have measured the activities of dust toward nuclear hormone receptors using cell-based assays (Chou et al 2015;Fang et al 2015;Hamers et al 2020;Kassotis et al 2019;Suzuki et al 2007;Vandermarken et al 2016). For example, Suzuki et al (2013) reported that certain measured PBDEs or OPEs in household dust were probable contributors to ERa activation and AR suppression.…”

Section: Introductionmentioning

confidence: 99%

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Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays

Young

Zoeller

Hauser

et al. 2021

Environ Health Perspect

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Background: Per- and polyfluoroalkyl substances (PFAS), organophosphate esters (OPEs), and polybrominated diphenyl ethers (PBDEs) are hormone-disrupting chemicals that migrate from building materials into air and dust. Objectives: We aimed to quantify the hormonal activities of 46 dust samples and identify chemicals driving the observed activities. Methods: We evaluated associations between hormonal activities of extracted dust in five cell-based luciferase reporter assays and dust concentrations of 42 measured PFAS, OPEs, and PBDEs, transformed as either raw or potency-weighted concentrations based on Tox21 high-throughput screening data. Results: All dust samples were hormonally active, showing antagonistic activity toward peroxisome proliferator-activated receptor ( ) (100%; 46 of 46 samples), thyroid hormone receptor ( ) (89%; 41 samples), and androgen receptor (AR) (87%; 40 samples); agonist activity on estrogen receptor ( ) (96%; 44 samples); and binding competition with thyroxine ( ) on serum transporter transthyretin (TTR) (98%; 45 samples). Effects were observed with as little as of extracted dust. In regression models for each chemical class, interquartile range increases in potency-weighted or unknown-potency chemical concentrations were associated with higher hormonal activities of dust extracts (potency-weighted: , , ; , , ; , , ; , , ; unknown-potency: , , ; , , ), adjusted for chemicals with active, inactive, and unknown Tox21 designations. Discussion: All indoor dust samples exhibited hormonal activities, which were associated with PFAS, PBDE, and OPE levels. Reporter gene cell-based assays are relatively inexpensive, health-relevant evaluations of toxic loads of chemical mixtures that building occupants are exposed to. https://doi.org/10.1289/EHP8054

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Section: Methods Evaluation Of Potency-weighted Concentrations Of Chemical Classesmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays

Young

Zoeller

Hauser

et al. 2021

Environ Health Perspect

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“…A recent follow-up to this study evaluated the adipogenic activity of 137 house dust extracts from central NC households and attempted to determine putative causative chemicals, molecular mechanisms, and potential impacts on human metabolic health (264). We reported that 90% of the dust extracts exhibited significant adipogenic activity, < 60% via significant triglyceride accumulation, and >70% of samples via significant pre-adipocyte proliferation, with >40% of effects occurring at < 10 μg dust/well (264). Increasing dust-induced triglyceride accumulation was positively correlated with serum thyroid stimulating hormone levels in adult residents, and negatively correlated with serum free triiodothyronine (T3) and thyroxine (T4) (264).…”

Section: Metabolic Disruption Potential Of Environmental Mixturesmentioning

confidence: 99%

“…We reported that 90% of the dust extracts exhibited significant adipogenic activity, < 60% via significant triglyceride accumulation, and >70% of samples via significant pre-adipocyte proliferation, with >40% of effects occurring at < 10 μg dust/well (264). Increasing dust-induced triglyceride accumulation was positively correlated with serum thyroid stimulating hormone levels in adult residents, and negatively correlated with serum free triiodothyronine (T3) and thyroxine (T4) (264). Interestingly, proliferation tended to be positively correlated with residents' body mass index (BMI; p < 0.10), potentially suggesting adipogenic chemicals present in the dust are associated with the weights of residents, but further research with larger sample sizes are needed to substantiate this.…”

Section: Metabolic Disruption Potential Of Environmental Mixturesmentioning

confidence: 99%

“…Interestingly, proliferation tended to be positively correlated with residents' body mass index (BMI; p < 0.10), potentially suggesting adipogenic chemicals present in the dust are associated with the weights of residents, but further research with larger sample sizes are needed to substantiate this. We further assessed TR antagonism as a potential contributory causative mechanism in these effects, and found that TRβ antagonism of these extracts (265) was positively correlated with triglyceride accumulation (264). Both T3 co-treatment and siRNA knock-down of TR inhibited the dust-induced triglyceride accumulation of these extracts, supporting the role of TR antagonism as a contributory molecular mechanism.…”

Section: Metabolic Disruption Potential Of Environmental Mixturesmentioning

confidence: 99%

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Endocrine-Mediated Mechanisms of Metabolic Disruption and New Approaches to Examine the Public Health Threat

Kassotis

Stapleton

2019

Front. Endocrinol.

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Obesity and metabolic disorders are of great societal concern and generate substantial human health care costs globally. Interventions have resulted in only minimal impacts on disrupting this worsening health trend, increasing attention on putative environmental contributors. Exposure to numerous environmental contaminants have, over decades, been demonstrated to result in increased metabolic dysfunction and/or weight gain in cell and animal models, and in some cases, even in humans. There are numerous mechanisms through which environmental contaminants may contribute to metabolic dysfunction, though certain mechanisms, such as activation of the peroxisome proliferator activated receptor gamma or the retinoid x receptor, have received considerably more attention than less-studied mechanisms such as antagonism of the thyroid receptor, androgen receptor, or mitochondrial toxicity. As such, research on putative metabolic disruptors is growing rapidly, as is our understanding of molecular mechanisms underlying these effects. Concurrent with these advances, new research has evaluated current models of adipogenesis, and new models have been proposed. Only in the last several years have studies really begun to address complex mixtures of contaminants and how these mixtures may disrupt metabolic health in environmentally relevant exposure scenarios. Several studies have begun to assess environmental mixtures from various environments and study the mechanisms underlying their putative metabolic dysfunction; these studies hold real promise in highlighting crucial mechanisms driving observed organismal effects. In addition, high-throughput toxicity databases (ToxCast, etc.) may provide future benefits in prioritizing chemicals for in vivo testing, particularly once the causative molecular mechanisms promoting dysfunction are better understood and expert critiques are used to hone the databases. In this review, we will review the available literature linking metabolic disruption to endocrine-mediated molecular mechanisms, discuss the novel application of environmental mixtures and implications for in vivo metabolic health, and discuss the putative utility of applying high-throughput toxicity databases to answering complex organismal health outcome questions.

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Organophosphate Esters: Are These Flame Retardants and Plasticizers Affecting Children’s Health?

Doherty

Hammel

Daniels

et al. 2019

Curr Envir Health Rpt

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Thyroid receptor antagonism as a contributory mechanism for adipogenesis induced by environmental mixtures in 3T3-L1 cells

Cited by 21 publications

References 78 publications

Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays

Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays

Endocrine-Mediated Mechanisms of Metabolic Disruption and New Approaches to Examine the Public Health Threat

Organophosphate Esters: Are These Flame Retardants and Plasticizers Affecting Children’s Health?

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