In vitro assessment of human nuclear hormone receptor activity and cytotoxicity of the flame retardant mixture FM 550 and its triarylphosphate and brominated components

Abstract

Firemaster® 550 (FM 550) is a mixture of brominated and triarylphosphate flame retardants used in polyurethane foam-based products. The primary components are also used in numerous other applications and are thus common household and industrial contaminants. Our previous animal studies suggested that FM 550 exposure may alter metabolism and cause weight gain. Employing human nuclear receptor (NR) luciferase reporter assays, the goal of this study was to evaluate the agonist actions of FM 550 and its constituent compounds at NRs with known roles in establishing or regulating energy balance. FM 550 was found to have significant agonist activity only at the master regulator of adipocyte differentiation PPARγ. As a result, the concentration response relationships and relative activities of FM 550 at PPARγ were investigated in more detail with the contribution of each chemical component defined and compared to the activities of the prototypical PPARγ environmental ligands triphenyltin and tributylytin. The resulting data indicated that the primary metabolic disruptive effects of FM 550 were likely mediated by the activity of the triarylphosphates at PPARγ, and have identified TPP as a candidate metabolic disruptor that also acts as a cytotoxicant.

Exposures, mechanisms, and impacts of endocrine-active flame retardants

“…While limited to only one study, this perinatal exposure suggests that exposure to FM 550 can alter adipogenic and developmental pathways. As a follow-up to this study, researchers also investigated the effects of FM 550 and its individual components on nuclear receptor activation [77*] and adipogenic and osteogenic pathways in cell culture [78*]. Combined results from these studies suggest that FM 550, and particularly TPP, may be eliciting an obesogenic phenotype due to activation of the nuclear receptor PPARγ and upregulation of adipogenesis, which may occur at the expense of osteogenesis.…”

In vitro assessment of thyroid hormone receptor activity of four organophosphate esters

“…Furthermore, the human aryl hydrocarbon receptor (AhR), human constitutively active receptor and human pregnane X receptor (PXR) pathways were found to be affected by OPEs (Gerlach et al, 2014;Honkakoski et al, 2004). The results of two recent studies suggested that some of these OPE compounds could exert their toxicity via the activation of the peroxisome proliferator-activated receptor (PPARγ) pathway (Belcher et al, 2014;Fang et al, 2015). Furthermore, Kojima et al (2013) evaluated the effects of OPEs against eight human nuclear receptor pathways and found that four of these pathways were affected by the OPEs:ER agonistic activity, androgen receptor antagonistic activity, glucocorticoid receptor antagonistic activity and PXR agonistic activity.…”

Formation and characterization of an inclusion complex of triphenyl phosphate and β-cyclodextrin and its use as a flame retardant for polyethylene terephthalate

“…Belcher and coworkers studied the structural similarities between TPP and triphenyl tin (TPT) chloride, whose structures are given in Figure 1. TPT chloride is a favorable ligand for peroxisome proliferator-activated receptor gamma (PPARγ) from the endocrine system, as well as a metabolic disruptor (12), and thus they speculated that, in a way similar to organotin chemicals, TPP may play a role in the obesogenic effects caused by FM 550 exposure. Pillai and coworkers confirmed that TPP increased human PPARγ transcriptional activity, and thus through environmental exposure, it may potentially lead to obesity and osteoporosis in humans (13).…”