SAT-243 - Disruption of Glucose Homeostasis and Hepatic Metabolic Pathways by Tris(1,3-Dichloro-2-Propyl) Phosphate Is Not PXR-Dependent in Mice.

Organophosphate flame retardants such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are widespread environmental contaminants associated with metabolic dysfunction. Our previous studies demonstrate that TDCPP exposure induces metabolic dysfunction, specifically hepatic insulin resistance assessed by hyperinsulinemic–euglycemic clamp, identifying the liver as a critical target tissue. Nuclear receptor screening of over 20 receptors identified both mouse and human pregnane X receptor (PXR) as the only significantly activated targets of TDCPP. Based on these findings, we hypothesized that TDCPP induces metabolic dysfunction via hepatic PXR signaling.

Wild-type and PXR knockout (PXRKO) littermates were maintained for 10–11 weeks on a control diet containing vehicle (7% corn oil), TDCPP (415 ppm; ~50 mg/kg body weight/day), or the PXR agonist pregnenolone-16α-carbonitrile (PCN; 283.8 ppm; ~34 mg/kg body weight/day). Body weight and food intake were measured weekly, with body weights balanced between treatment groups at baseline. Metabolic phenotyping, including body composition analysis and glucose tolerance tests (GTT), was initiated after 5 weeks of exposure. Fasting glucose and insulin concentrations were quantified from blood collected during submandibular bleeds. After 11 weeks of exposure, mice were euthanized and livers were collected, weighed, and snap frozen; hepatic triglycerides and alanine aminotransferase (ALT) were quantified. Quantitative PCR was used to assess hepatic mRNA expression of genes related to xenobiotic and macronutrient metabolism. Western blot analyses were performed to confirm hepatic PXR expression, activation, and to evaluate PXR-mediated effects in wild-type versus PXRKO mice.

TDCPP exposure impaired glucose tolerance and insulin responsiveness in male mice, with effects persisting in PXRKO animals. TDCPP exposure was associated with changes in hepatic metabolic gene expression and metabolic endpoints, several of which were maintained in the absence of PXR. In contrast, PCN exposure induced expected PXR-responsive gene expression without recapitulating the broader TDCPP-associated metabolic phenotype. Female mice displayed limited metabolic responses to TDCPP.

Together, these findings indicate that although TDCPP activates PXR, TDCPP-induced metabolic dysfunction is not mediated through PXR signaling. TDCPP is also an androgen receptor antagonist; inhibition of this nuclear receptor may contribute to male-specific metabolic impairments. We also acknowledge the likelihood that nuclear receptor–independent mechanisms may contribute to the observed metabolic phenotype.

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