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Phthalate exposure changes the metabolic profile of cardiac muscle cells.

ABSTRACT: 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.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.Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50-100 ?g/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.Exposure to DEHP led to up-regulation of genes associated with fatty acid transport, esterification, mitochondrial import, and ?-oxidation. The functional outcome was an increase in myocyte fatty acid-substrate utilization, oxygen consumption, mitochondrial mass, PPAR? (peroxisome proliferator-activated receptor ?) protein expression, and extracellular acidosis. Treatment with a PPAR? agonist (Wy-14643) only partially mimicked the effects observed in DEHP-treated cells.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.

SUBMITTER: Posnack NG

PROVIDER: S-EPMC3440133 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Phthalate exposure changes the metabolic profile of cardiac muscle cells.

Posnack Nikki Gillum NG Swift Luther M LM Kay Matthew W MW Lee Norman H NH Sarvazyan Narine N

Environmental health perspectives 20120606 9

<h4>Background</h4>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.<h4>Objectives</h4>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.< ...[more]

PMID: 22672789

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Project description:Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.

Project description:Bioenergetics of artery smooth muscle cells is critical in cardiovascular health and disease. An acute rise in metabolic demand causes vasodilation in systemic circulation while a chronic shift in bioenergetic profile may lead to vascular diseases. A decrease in intracellular ATP level may trigger physiological responses while dedifferentiation of contractile smooth muscle cells to a proliferative and migratory phenotype is often observed during pathological processes. Although it is now possible to dissect multiple building blocks of bioenergetic components quantitatively, detailed cellular bioenergetics of artery smooth muscle cells is still largely unknown. Thus, we profiled cellular bioenergetics of human coronary artery smooth muscle cells and effects of metabolic intervention. Mitochondria and glycolysis stress tests utilizing Seahorse technology revealed that mitochondrial oxidative phosphorylation accounted for 54.5% of ATP production at rest with the remaining 45.5% due to glycolysis. Stress tests also showed that oxidative phosphorylation and glycolysis can increase to a maximum of 3.5 fold and 1.25 fold, respectively, indicating that the former has a high reserve capacity. Analysis of bioenergetic profile indicated that aging cells have lower resting oxidative phosphorylation and reduced reserve capacity. Intracellular ATP level of a single cell was estimated to be over 1.1 mM. Application of metabolic modulators caused significant changes in mitochondria membrane potential, intracellular ATP level and ATP:ADP ratio. The detailed breakdown of cellular bioenergetics showed that proliferating human coronary artery smooth muscle cells rely more or less equally on oxidative phosphorylation and glycolysis at rest. These cells have high respiratory reserve capacity and low glycolysis reserve capacity. Metabolic intervention influences both intracellular ATP concentration and ATP:ADP ratio, where subtler changes may be detected by the latter.

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Phthalate exposure changes the metabolic profile of cardiac muscle cells.

Publications

Phthalate exposure changes the metabolic profile of cardiac muscle cells.

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