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.
Status | Active |
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Effective start/end date | 7/1/24 → 6/30/29 |
Funding
- National Institute of Environmental Health Sciences: $429,135.00
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