期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 24, 页码 -出版社
MDPI
DOI: 10.3390/ijms222413489
关键词
DEHP; 2-ethylhexanol; CoA; CoA esters; lipid metabolism
资金
- NIH [R33DK070291, R01ES013925]
- American Heart Association [12GRNT12050453]
DEHP, a common plasticizer, is a metabolic disrupter that affects the production and sequestration of CoA, an essential cofactor for oxidative and biosynthetic reactions. Exposure to DEHP led to significantly increased hepatic levels of free CoA and various CoA esters, particularly the physiological CoA ester of malonyl-CoA and the DEHP-derived CoA ester of 3-keto-2-ethylhexanoyl-CoA.
Di(2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in various industrial and household plastic products, ensuring widespread human exposures. Its routine detection in human bio-fluids and the propensity of its monoester metabolite to activate peroxisome proliferator activated receptor-alpha (PPAR alpha) and perturb lipid metabolism implicate it as a metabolic disrupter. In this study we evaluated the effects of DEHP exposure on hepatic levels of free CoA and various CoA esters, while also confirming the metabolic activation to CoA esters and partial beta-oxidation of a DEHP metabolite (2-ethyhexanol). Male Wistar rats were exposed via diet to 2% ((w)/(w)) DEHP for fourteen-days, following which hepatic levels of free CoA and various CoA esters were identified using liquid chromatography-mass spectrometry. DEHP exposed rats showed significantly elevated free CoA and increased levels of physiological, DEHP-derived and unidentified CoA esters. The physiological CoA ester of malonyl-CoA and DEHP-derived CoA ester of 3-keto-2-ethylhexanoyl-CoA were the most highly elevated, at eighteen- and ninety eight-times respectively. We also detected sixteen unidentified CoA esters which may be derivative of DEHP metabolism or induction of other intermediary metabolism metabolites. Our results demonstrate that DEHP is a metabolic disrupter which affects production and sequestration of CoA, an essential cofactor of oxidative and biosynthetic reactions.
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