title: Di-(2-ethylhexyl) phthalate accelerates atherosclerosis in apolipoprotein E-deficient mice.
abstract: Di-(2-ethylhexyl) phthalate (DEHP) is associated with atherosclerosis-related cardiovascular disease complications, but we lack direct evidence of its unfavorable effect on atherogenesis. In this study, we aimed to clarify in vivo and in vitro the contribution of DEHP to the development of atherosclerosis and its underlying mechanisms. Apolipoprotein E-deficient (apoE(-/-)) mice chronically treated with DEHP for 4 weeks showed exacerbated hyperlipidemia, systemic inflammation, and atherosclerosis. In addition, DEHP promoted low-density lipoprotein (LDL) oxidation, which led to inflammation in endothelial cells as evidenced by increased protein expression of pro-inflammatory mediators. Furthermore, chronic DEHP treatment increased hepatic cholesterol accumulation by downregulating the protein expression of key regulators in cholesterol clearance including LDL receptor, cholesterol 7α-hydrolase, ATP-binding cassette transporter G5 and G8, and liver X receptor α. Moreover, the adiposity and inflammation of white adipose tissues were promoted in DEHP-treated apoE(-/-) mice. In conclusion, DEHP may disturb cholesterol homeostasis and deregulate the inflammatory response, thus leading to accelerated atherosclerosis.
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Ren-Ai Taipei City Hospital, Taipei, 10629, Taiwan.
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Hsiao
authors.affiliation: Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, 30013, Taiwan.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Hsu
authors.affiliation: Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, 30013, Taiwan.
authors.forename: Kuan-Chuan
authors.initials: KC
authors.lastname: Pao
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
authors.affiliation: Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan. tslee@ym.edu.tw.
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D010641:Phenotype; D010968:Plasticizers / Q000633:toxicity*; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D010968:Plasticizers; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D004051:Diethylhexyl Phthalate
keywords: Atherosclerosis; Cholesterol metabolism; DEHP; Inflammation; Obesity