Tris(1,3-dichloro-2-propyl) phosphate is a metabolism-disrupting chemical in male mice

• Published in: Toxicology letters 2023-02, Vol.374, p.31-39
• Main Authors: Tenlep, Sara Y. Ngo, Weaver, Megan, Chen, Jianzhong, Vsevolozhskaya, Olga, Morris, Andrew J., Rashid, Cetewayo S.
• Format: Article
• Language: English
• Subjects: Animals; Body composition; Diabetes Mellitus, Type 2 - epidemiology; Female; Flame Retardants - metabolism; Flame Retardants - toxicity; Glucose tolerance; Humans; Insulin Resistance; Male; Metabolic Syndrome - chemically induced; Metabolic Syndrome - epidemiology; Metabolic Syndrome - urine; Mice; Mice, Inbred C57BL; Nuclear receptor; Organophosphate flame retardant; Organophosphorus Compounds - metabolism; Organophosphorus Compounds - toxicity; Organophosphorus Compounds - urine; Receptors, Cytoplasmic and Nuclear - metabolism; TDCPP
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2022.11.021

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. •Dietary TDCPP exposure in C57Bl/6J mice did not affect body weight but did cause male sex-specific adiposity.•Dietary TDCPP exposure caused male sex-specific insulin resistance and fasting hyperglycemia.•TDCPP significantly activated farnesoid X receptor (FXR) and both mouse and human pregnane X receptors (PXR) in vitro.•In livers, TDCPP caused differential gene expression of PXR target genes, but not FXR target genes.•TDCPP significantly inhibited the androgen receptor in vitro, but there was no difference in testes weight.