Phthalate Exposure Changes the Metabolic Profile of Cardiac Muscle Cells

Posnack, Nikki Gillum; Swift, Luther; Kay, Matthew W.; Lee, Norman H.; Sarvazyan, Narine

doi:10.1289/ehp.1205056

Cited by 89 publications

(59 citation statements)

References 38 publications

(53 reference statements)

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“…This concentration of DEHP was comparable to the levels found in dairy products [42]. Considering the potential disruptive effects on human metabolism of DEHP exposure [43], carbohydrate and lipid levels were analysed. Flies from control and 200 lM DEHP-fed groups were collected and starved for 24 hr.…”

Section: Dehp Affects Lipid and Circulating Carbohydrate Levelssupporting

confidence: 67%

Bis‐(2‐ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster

Cao

Wiemerslage

Marttila

et al. 2016

Basic Clin Pharma Tox

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Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that longterm DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions.Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers in manufacturing polyvinyl chloride (PVC) products [1]. Marked leaching into the environment occurs because phthalates are not covalently bound to the polymeric matrix. Human exposure to DEHP can occur via many routes, such as medical equipment, food containers and beverages, including drinking water. Although there are some limitations of using DEHP in food and devices, human exposure to excess DEHP is common. According to the United States Food and Drug Administration (FDA), medical devices made with PVC release DEHP into the body at levels up to 10 times higher than the tolerable daily intake (TDI) level [2]. In 2010, a review by the European Chemicals Agency (ECHA) announced that high levels of DEHP metabolites were detected in breastmilk, urine and other body fluid samples [3][4][5], while a survey conducted in Germany showed approximately 12% of the population exceeded the TDI value [6]. Thus, investigating how DEHP may disrupt metabolism is an important human health issue.Chronic exposure to DEHP and its oxidized metabolites may disrupt metabolism [7]. A study in rats found evidence that DEHP causes insulin resistance in adipose tissue via oxidation of glucose [8]. Studies also suggest that exposure to DEHP may affect mammalian reproductive ability [9-11] and development [12,13]. In human beings, DEHP metabolites, such as mono(2-ethyl-5-oxo-hexyl) phthalate (5oxo-MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP) and mono (2-ethyl-5-hydroxyhexyl) phthalate (6-OH-MEHP), which increase in urine with age and weight [14], positively correlate with obesity and insulin resistance [15,16].Importantly, in children aged less than 3 months, the glucuronidation pathway is still immature, which may cause increased internal concentrations of these toxic metabolites [17,18].However, it is unclear how DEHP interferes with metabolic pathways. To investigate the disruptive effects of DEHP, we employed Drosophila melanogast...

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Section: Dehp Affects Lipid and Circulating Carbohydrate Levelssupporting

confidence: 67%

Bis‐(2‐ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster

Cao

Wiemerslage

Marttila

et al. 2016

Basic Clin Pharma Tox

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“…Totally, it could be said that the present study provides the first report about the effects of PA, during pregnancy, on the geometry of coronary vessels, oxidative stress of the cardiac tissue, and the NOS activity of the thoracic aorta. It is still unknown that the vascular or cardiotoxicity observed in offspring is a result of direct effects of maternal transfer of phthalic acid or its metabolites and it has been previously explained by different studies in animal or human models [48][49][50]. Studies on health effects of PAEs in humans have remained controversial due to limitations of the study designs.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Exposure to Phthalic Acid Induces Increased Blood Pressure, Oxidative Stress, and Markers of Endothelial Dysfunction in Rat Offspring

et al. 2015

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Previous studies have reported the harmful effects of exposure to phthalic acid (PA) on heart. No studies have reported the effects of prenatal PA exposure on the structure or function of heart. The current study aimed to investigate the effects of prenatal PA exposure on the markers of oxidative stress and cardiac structure in rats' offspring. Twenty-four pregnant rats were randomly categorized into three groups of control, exposed to 2.5 and 5 % PA. The morphometric properties of coronary arteries, markers of oxidative stress, and NOS activity were measured in offspring rats. By a dose-dependent manner, the body weight (BW), heart weight (HW), and HW/BW of the intervention groups were reduced and their heart rate and blood pressure were conversely increased compared to the control group. Also, the wall thickness, cross-sectional area of the aorta and septal branch of the descending left coronary artery were significantly increased in the intervention group. In addition, PA significantly increased the level of malondialdehyde and decreased the level of superoxide dismutase and glutathione peroxidase, compared to the control group. This study revealed that prenatal exposure of rats to PA causes vascular dysfunction, increasing oxidative stress, and reduction in cardiac nitric oxide synthetase activity among offspring rats.

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“…Phthalates simultaneously affects multiple cellular targets, 50 and produce changes in the metabolic profile of cardiac cells 51 as well as oxidative stress. 14 Phthalates can also have additional, indirect effects on cardiovascular risk, as women exposed to phthalates during pregnancy have been shown to have significantly increased odds of delivering preterm 52 and the link between preterm birth (gestational age) and hypertension risk is clear and well established.…”

Section: Perspectivesmentioning

confidence: 99%

Association of Exposure to Di-2-Ethylhexylphthalate Replacements With Increased Blood Pressure in Children and Adolescents

Trasande

Attinà

2015

Hypertension

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Phthalates are environmental chemicals widely used in consumer and personal care products. In this study we examined associations of urinary phthalates with blood pressure, triglycerides and lipoproteins in children and adolescents, performing a cross-sectional analysis of a subsample of US children 6–19 years of age who participated in the National Health and Nutrition Examination Survey between the years 2009–2012. We quantified exposure to common environmental phthalates, with a focus on the dietary contaminant di-2-ethylhexylphthalate and two increasingly used replacements, di-isononyl phthalate and di-isodecyl phthalate, based on micromolar concentration of urinary metabolites. We assessed descriptive, univariate and multivariable associations with blood pressure and lipids. Controlling for an array of sociodemographic and behavioral factors, as well as diet and body mass, metabolites of di-2-ethylhexylphthalate , di-isononyl phthalate and di-isodecyl phthalate were associated with higher age-, gender- and height-standardized blood pressure. For each log unit increase in di-isodecyl phthalate metabolites, a 0.105 standard deviation unit increase in systolic blood pressure z score was identified (p=0.004); for di-isononyl phthalate metabolites, a 0.113 standard deviation unit increment was identified (p=0.008). For di-2-ethylhexylphthalate metabolites, a 0.103 standard deviation unit increment (p=0.013) was detected. Metabolites of low molecular weight phthalates commonly found in cosmetics and personal care products showed an association with blood pressure (≥90th percentile) in univariate analysis, but this was no longer significant in our full multivariable model, suggesting specificity. Phthalate metabolites were not associated with triglycerides or high-density lipoproteins. Further, longitudinal studies are needed to confirm these associations, and to assess opportunities for intervention.

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Phthalate Exposure Changes the Metabolic Profile of Cardiac Muscle Cells

Cited by 89 publications

References 38 publications

Bis‐(2‐ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster

Bis‐(2‐ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster

Prenatal Exposure to Phthalic Acid Induces Increased Blood Pressure, Oxidative Stress, and Markers of Endothelial Dysfunction in Rat Offspring

Association of Exposure to Di-2-Ethylhexylphthalate Replacements With Increased Blood Pressure in Children and Adolescents

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