Phthalate exposure changes the metabolic profile of cardiac muscle cells.
BACKGROUND
Phthalates are common plasticizers present in medical-grade plastics and other everyday products. They can also act as endocrine-disrupting chemicals and have been linked to the rise in metabolic disorders. However, the effect of phthalates on cardiac metabolism remains largely unknown.


OBJECTIVE
We examined the effect of di(2-ethylhexyl)phthalate (DEHP) on the metabolic profile of cardiomyocytes because alterations in metabolic processes can lead to cell dysfunction.


METHODS
Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50-100 μg/mL, 72 hr). We assessed the effect of DEHP on gene expression using microarray analysis. Physiological responses were examined via fatty acid utilization, oxygen consumption, mitochondrial mass, and Western blot analysis.


RESULTS
Exposure to DEHP led to up-regulation of genes associated with fatty acid transport, esterification, mitochondrial import, and β-oxidation. The functional outcome was an increase in myocyte fatty acid-substrate utilization, oxygen consumption, mitochondrial mass, PPARα (peroxisome proliferator-activated receptor α) protein expression, and extracellular acidosis. Treatment with a PPARα agonist (Wy-14643) only partially mimicked the effects observed in DEHP-treated cells.


CONCLUSIONS
Data suggest that DEHP exposure results in metabolic remodeling of cardiomyocytes, whereby cardiac cells increase their dependence on fatty acids for energy production. This fuel switch may be regulated at both the gene expression and posttranscription levels. Our findings have important clinical implications because chronic dependence on fatty acids is associated with an accumulation in lipid intermediates, lactate, protons, and reactive oxygen species. This dependence can sensitize the heart to ischemic injury and ventricular dysfunction.
Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA. nikkigillum@gmail.com
Nikki Gillum
NG
Posnack
Luther M
LM
Swift
Matthew W
MW
Kay
Norman H
NH
Lee
Narine
N
Sarvazyan
D000818:Animals; D015153:Blotting, Western; D004051:Diethylhexyl Phthalate / Q000378:metabolism / Q000633:toxicity*; D004785:Environmental Pollutants / Q000378:metabolism / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism; D010968:Plasticizers / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D046888:Tissue Array Analysis
D004785:Environmental Pollutants; D005227:Fatty Acids; D047493:PPAR alpha; D010968:Plasticizers; D004051:Diethylhexyl Phthalate; D005947:Glucose