ABSTRACT
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate flame retardant. The primary TDCPP metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), is detectable in the urine of over 90 % of Americans. Epidemiological studies show sex-specific associations between urinary BDCPP levels and metabolic syndrome, which is an established risk factor for type 2 diabetes, heart disease, and stroke. We used a mouse model to determine whether TDCPP exposure disrupts glucose homeostasis. Six-week old male and female C57BL/6J mice were given ad libitum access to diets containing vehicle (0.1 % DMSO) and TDCPP resulting in the following treatment groups: 0 mg/kg/day, 0.02 mg/kg/day, 1 mg/kg/day, or 100 mg/kg/day. After being on the experimental diet for five weeks without interruption, body composition was analyzed, glucose and insulin tolerance tests were performed, and fasting glucose and insulin levels were quantified. TDCPP at 100 mg/kg/day caused male sex-specific adiposity, fasting hyperglycemia, and insulin resistance. TDCPP-induced modulation of nuclear receptor activation was investigated using an in vitro screen to identify potential mechanisms of metabolic disruption. TDCPP activated farnesoid X receptor (FXR) and pregnane X receptor (PXR), and inhibited the androgen receptor (AR). PXR target genes, but not FXR target genes, were upregulated in livers from mice exposed to 100 mg TDCPP/kg/day. Interestingly, PXR target genes were differentially expressed in livers from both males and females. It remains to be determined whether TDCPP-induced metabolic disruption occurs via modulation of nuclear receptor activity. Taken together, these studies build upon the association of TDCPP exposure and metabolic syndrome in humans by identifying sex-specific effects of TDCPP on glucose homeostasis in mice.
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Date of publication: 24 December 2022; Toxicolgoy Letters
Author information: Sara Y Ngo Tenlep (1), Megan Weaver (1), Jianzhong Chen (2), Olga Vsevolozhskaya (3), Andrew J Morris (4), Cetewayo S Rashid (5)
(1) Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
(2) Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
(3) Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
(4) Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, KY, USA; Lexington Veterans Affairs Healthcare System, Lexington, KY, USA.
(5) Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA.