Abstract
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-α (PPARα) 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 β-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.
Highlights
Phthalate esters are commonly used as plasticizers in various industrial and household plastic products [1,2,3,4,5,6,7,8]
Di(2-ethylhexyl) phthalate (DEHP) acts as a metabolic disrupter and hepatic toxicant as its monoester metabolite, mono(2-ethylhexyl) phthalate (Figure 1), can bind to and activate peroxisome proliferator-activated receptors (PPARs), peroxisome proliferator activated receptor-α (PPARα) and
Our results show that exposure to 2% DEHP induced a significant (10-times) increase in free CoA concentration relative to Control
Summary
Phthalate esters are commonly used as plasticizers in various industrial and household plastic products [1,2,3,4,5,6,7,8]. Central amongst phthalate esters is di(2-ethylhexyl) phthalate or DEHP, which along with its various metabolites, is commonly detected in the blood plasma and urine of children and adults in the general population [9,10,11,12,13,14]. DEHP acts as a metabolic disrupter and hepatic toxicant as its monoester metabolite, mono(2-ethylhexyl) phthalate (or MEHP) (Figure 1), can bind to and activate peroxisome proliferator-activated receptors (PPARs), PPARα and 4.0/).
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