Tris(1,3‐Dichloro‐2‐Propyl)Phosphate Is an Endocrine Disrupting Compound Causing Sex‐Specific Changes in Body Composition and Insulin Sensitivity

Abstract

Organophosphate flame retardants are used on polyurethane foams and off-gassing leads to ubiquitous environmental exposure. Tris(1,3-dichloro-2-propyl)phosphate (TDCPP) is one of several organophosphate flame retardants, and its use and accumulation in indoor spaces has been steadily increasing over the past decade. However, the impact of TDCPP exposure on human health is unknown, especially as it relates to metabolic disorders. The objective of the present study, therefore, was to test whether TDCPP exposure causes metabolic disruption. Beginning at 6 weeks of age, male and female C57BL/6 mice (N = 4-10 per group) were given ad libitum access to purified diets with either vehicle (0.1% w/w DMSO) or one of three doses of TDCPP (Low, 0.02 mg/kg/day; Medium, 1 mg/kg/day; High, 50 mg/kg/day). After 5 weeks of dietary exposure, body weights were comparable between groups, yet, body composition as determined by quantitative magnetic resonance revealed dose-dependent increase in percent body fat and decrease in percent lean mass in male mice. Intraperitoneal glucose tolerance testing showed no effect of TDCPP exposure. However, insulin tolerance tests showed severe insulin resistance in the High dose males while females were unaffected. In vitro reporter assays were used to determine TDCPP (1 nM, 0.1 µM, and 100 µM) agonist activity on 26 nuclear receptors. Reporter cells expressed either native receptor or receptor hybrids in which Gal4 DNA binding domain replaced native DNA binding domains. Firefly luciferase was functionally linked downstream of receptor-specific response elements or Gal4 upstream activating sequence. Of note, TDCPP did not affect cell viability at any of the concentrations tested. Compared to DMSO vehicle control, the 100 µM TDCPP caused activation of both human and mouse pregnane X receptors (16-fold increase) and farnesoid X receptor (2.5-fold increase). Interestingly, the 100 µM TDCPP also caused a 60% reduction in estrogen receptor alpha and vitamin D receptor luminescence. Taken together, these studies show TDCPP is an endocrine disrupting compound that causes sex-specific body composition maladaptations and insulin resistance. Future studies will determine whether these nuclear receptors are mediating metabolic disruption in vivo.