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.