Mechanisms of Sex-specific Metabolic Disruption Caused by Organophosphate Flame Retardant Exposure

Grants and Contracts Details

Description

Project Abstract: Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate flame retardant used to meet federal and state flammability standards of various consumer products. Off-gassing causes TDCPP to accumulate in dust and contaminate indoor spaces. TDCPP is stable in the environment, but when it enters the body, which is most commonly via hand-to-mouth contact, TDCPP is readily metabolized to bis(1,3-dichloro-2- propyl) phosphate (BDCPP). Ninety percent of Americans have detectable BDCPP in their urine, indicating ubiquitous exposure. Studies utilizing data from the National Health and Nutrition Examination Survey found a significant positive association between urinary BDCPP levels and metabolic syndrome, with the components central adiposity and hyperglycemia carrying the association. Interestingly, the association with BDCPP and metabolic syndrome was found only in men. We have developed a mouse model of TDCPP exposure that reproduces male sex-specific metabolic disruption. TDCPP is incorporated into purified low phytoestrogen diets to mimic the primary route of exposure in humans. When fed this diet, male mice have increased percent body fat and insulin resistance. Euglycemic clamp showed insulin resistance was liver-specific. We screened TDCPP in vitro for agonist activity against 26 nuclear receptors and found that TDCPP activates only farnesoid X and pregnane X receptors (PXR). However, in livers of TDCPP-treated mice, only PXR target genes were differentially expressed. Building upon our preliminary findings, our proposed studies will test the overall hypothesis that PXR activation mediates male sex-specific TDCPP-induced hepatic insulin resistance. We will interrogate insulin action and signaling in livers of male and female mice. Using PXR-/- mice and dietary exposure to BDCPP, which is not a PXR agonist, we will determine whether PXR activation is necessary to confer metabolic disruption. We will gonadectomize male and female mice to determine whether TDCPP-induced metabolic disruption is sex hormone dependent. Finally, to further elucidate the mechanistic underpinnings of TDCPP’s sex-specific metabolic disruption, we will perform mRNA sequencing of livers of WT, PXR-/- and castrated male and female mice. The proposed preclinical studies fill a critical emergent knowledge gap regarding whether the ubiquitous environmental contaminant, TDCPP, promotes development of metabolic syndrome. Results from these studies will drive future knowledge toward interventions and screening strategies for metabolically innocuous flame retardants. Furthermore, our studies will progress our understanding of xenobiotic-mediated sex differences, which may be generalizable to many other endocrine disrupting chemicals.
StatusActive
Effective start/end date7/1/246/30/29

Funding

  • National Institute of Environmental Health Sciences: $429,135.00

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