Pregnane X Receptor Mediates Atherosclerosis Induced by Dicyclohexyl Phthalate in LDL Receptor-Deficient Mice

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 (PXR(ΔMye)LDLR(−/−)) and their control littermates (PXR(F/F)LDLR(−/−)) 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 PXR(F/F)LDLR(−/−) mice by 65% and 77%, respectively. By contrast, DCHP did not affect atherosclerosis development in PXR(ΔMye)LDLR(−/−) mice. Exposure to DCHP led to elevated expression of the scavenger receptor CD36 in macrophages and increased macrophage form cell formation in PXR(F/F)LDLR(−/−) 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.