Plastic-associated
endocrine disrupting chemicals (EDCs) have been implicated in the etiology of
cardiovascular disease (CVD) in humans, but the underlying mechanisms remain elusive.
Dicyclohexyl phthalate (
DCHP) is a widely used
phthalate plasticizer; whether and how exposure to
DCHP elicits adverse effects in vivo is mostly unknown. We previously reported that
DCHP is a potent
ligand of the
pregnane X receptor (PXR) which acts as a
xenobiotic sensor to regulate
xenobiotic metabolism. PXR also functions in macrophages to regulate
atherosclerosis development in animal models. In the current study,
LDL receptor-deficient mice with myeloid-specific PXR deficiency (PXRΔMyeLDLR-/-) and their control littermates (PXRF/FLDLR-/-) were used to determine the impact of
DCHP exposure on macrophage function and
atherosclerosis. Chronic exposure to
DCHP significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of PXRF/FLDLR-/- mice by 65% and 77%, respectively. By contrast,
DCHP did not affect
atherosclerosis development in PXRΔMyeLDLR-/- mice. Exposure to
DCHP led to elevated expression of the
scavenger receptor CD36 in macrophages and increased macrophage form cell formation in PXRF/FLDLR-/- mice. Our findings provide potential mechanisms underlying
phthalate-associated CVD risk and will ultimately stimulate further investigations and mitigation of the adverse effects of
plastic-associated EDCs on CVD risk in humans.