We previously demonstrated that indoor house dust extracts could induce adipogenesis in pre-adipocytes, suggesting a potential role for indoor contaminant mixtures in metabolic health. Herein, we investigated the potential role of thyroid receptor beta (TRβ) antagonism in adipogenic effects (dust-induced triglyceride accumulation and pre-adipocyte proliferation) following exposure to environmental mixtures (indoor house dust extracts). Concentrations of specific flame retardants were measured in extracts, and metabolic health information was collected from residents (n = 137). 90% of dust extracts exhibited significant adipogenic activity, >60% via triglyceride accumulation, and >70% via pre-adipocyte proliferation. Triglyceride accumulation was positively correlated with concentrations of each of twelve flame retardants, despite most being independently inactive; this suggests a putative role for co-exposures or mixtures. We further reported a positive correlation between dust-induced triglyceride accumulation and serum thyroid stimulating hormone concentrations, negative correlations with serum free triiodothyronine and thyroxine concentrations, and a positive and significant association between dust-induced triglyceride accumulation and residents' body mass index (BMI). We hypothesized that inhibition of TR antagonism might counteract these effects, and both addition of a TR agonist and siRNA knock-down of TR resulted in decreased dust-induced triglyceride accumulation in a subset of samples, bolstering this as a contributory mechanism. These results highlight a contributory role of environmental TR antagonism as a putative factor in metabolic health, suggesting that further research should evaluate this mechanism and determine whether in vitro adipogenic activity could have utility as a biomarker for metabolic health in residents.

House dust is a source of exposure to chemicals that can impact hormone regulation. This study was designed to evaluate the potential of house dust mixtures ( n = 137) to disrupt thyroid hormone nuclear receptor signaling in a cell-based reporter assay and to examine associations with thyroid hormones (TH) measured in residents of the homes. Approximately 41% of the extracts (ranging from 10.5 to 4.097 μg of dust/mL) significantly antagonized thyroid receptor β (TRβ) signaling by 20-67% relative to the hormone control. The concentrations of 12 flame retardants (FRs) quantified in the mixtures were significantly correlated with TRβ antagonism; however, they were inactive when tested individually. We hypothesize that the observed antagonism is due to mixture effects or unidentified compounds that co-occur with FRs. Dust extract potency was significantly associated with free thyroxine (FT4, r_s = -0.64, p < 0.001), suggesting that more potent dust samples are associated with higher FT4 levels in residents. Overall, these results suggest that house dust is a significant source of exposure to TH-disrupting chemicals, and TRβ may have a role in mediating effects of exposure on TH levels. Additional studies are needed to identify the chemical(s) driving the observed effects on TRβ and to determine if these changes lead to any adverse outcomes.

Research suggests that thyroid cancer incidence rates are increasing, and environmental exposures have been postulated to be playing a role. To explore this possibility, we conducted a pilot study to investigate the thyroid disrupting bioactivity of chemical mixtures isolated from personal silicone wristband samplers within a thyroid cancer cohort. Specifically, we evaluated TRβ antagonism of chemical mixtures extracted from wristbands (n = 72) worn by adults in central North Carolina participating in a case-control study on papillary thyroid cancer. Sections of wristbands were solvent-extracted and analyzed via mass spectrometry to quantify a suite of semivolatile chemicals. A second extract from each wristband was used in a bioassay to quantify TRβ antagonism in human embryonic kidney cells (HEK293/17) at concentrations ranging from 0.1 to 10% of the original extract (by volume). Approximately 70% of the sample extracts tested at a 1% extract concentration exhibited significant TRβ antagonism, with a mean of 30% and a range of 0-100%. Inhibited cell viability was noted in >20% of samples that were tested at 5 and 10% concentrations. Antagonism was positively associated with wristband concentrations of several phthalates, organophosphate esters, and brominated flame retardants. These results suggest that personal passive samplers may be useful in evaluating the bioactivities of mixtures that people contact on a daily basis. We also report tentative associations between thyroid receptor antagonism, chemical concentrations, and papillary thyroid cancer case status. Future research utilizing larger sample sizes, prospective data collection, and measurement of serum thyroid hormone levels (which were not possible in this study) should be utilized to more comprehensively evaluate these associations.

There is increasing evidence of a role for environmental contaminants in disrupting metabolic health in both humans and animals. Despite a growing need for well-understood models for evaluating adipogenic and potential obesogenic contaminants, there has been a reliance on decades-old in vitro models that have not been appropriately managed by cell line providers. There has been a quick rise in available in vitro models in the last ten years, including commercial availability of human mesenchymal stem cell and preadipocyte models; these models require more comprehensive validation but demonstrate real promise in improved translation to human metabolic health. There is also progress in developing three-dimensional and co-culture techniques that allow for the interrogation of a more physiologically relevant state. While diverse rodent models exist for evaluating putative obesogenic and/or adipogenic chemicals in a physiologically relevant context, increasing capabilities have been identified for alternative model organisms such as Drosophila, C. elegans, zebrafish, and medaka in metabolic health testing. These models have several appreciable advantages, including most notably their size, rapid development, large brood sizes, and ease of high-resolution lipid accumulation imaging throughout the organisms. They are anticipated to expand the capabilities of metabolic health research, particularly when coupled with emerging obesogen evaluation techniques as described herein.

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.