title: Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes.
abstract: BACKGROUND
  The pervasive nature of plastics has raised concerns about the impact of continuous exposure to plastic additives on human health. Of particular concern is the use of phthalates in the production of flexible polyvinyl chloride (PVC) products. Di-2-ethylhexyl-phthalate (DEHP) is a commonly used phthalate ester plasticizer that imparts flexibility and elasticity to PVC products. Recent epidemiological studies have reported correlations between urinary phthalate concentrations and cardiovascular disease, including an increased risk of high blood pressure and coronary risk. Yet, there is little direct evidence linking phthalate exposure to adverse effects in human cells, including cardiomyocytes.
  
  
  RESULTS
  The effect of DEHP on calcium handling was examined using monolayers of gCAMP3 human embryonic stem cell-derived cardiomyocytes, which contain an endogenous calcium sensor. Cardiomyocytes were exposed to DEHP (5 - 50 μg/mL), and calcium transients were recorded using a Zeiss confocal imaging system. DEHP exposure (24 - 72 hr) had a negative chronotropic and inotropic effect on cardiomyocytes, increased the minimum threshold voltage required for external pacing, and modified connexin-43 expression. Application of Wy-14,643 (100 μM), an agonist for the peroxisome proliferator-activated receptor alpha, did not replicate DEHP's effects on calcium transient morphology or spontaneous beating rate.
  
  
  CONCLUSIONS
  Phthalates can affect the normal physiology of human cardiomyocytes, including DEHP elicited perturbations in cardiac calcium handling and intercellular connectivity. Our findings call for additional studies to clarify the extent by which phthalate exposure can alter cardiac function, particularly in vulnerable patient populations who are at risk for high phthalate exposure.
authors: Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States of America.
authors: Nikki Gillum
authors: NG
authors: Posnack
authors: Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States of America.
authors: Rabia
authors: R
authors: Idrees
authors: Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States of America.
authors: Hao
authors: H
authors: Ding
authors: Department of Electrical & Computer Engineering, The George Washington University, Washington, DC, United States of America.
authors: Rafael
authors: R
authors: Jaimes
authors: Department of Biomedical Engineering, University of California Davis, Davis, CA, United States of America.
authors: Gulnaz
authors: G
authors: Stybayeva
authors: Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States of America.
authors: Zaruhi
authors: Z
authors: Karabekian
authors: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors: Michael A
authors: MA
authors: Laflamme
authors: Department of Pharmacology & Physiology, The George Washington University, Washington, DC, United States of America.
authors: Narine
authors: N
authors: Sarvazyan
mesh_terms: D002118:Calcium / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D011743:Pyrimidines / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: D018031:Connexin 43; D047492:Peroxisome Proliferator-Activated Receptors; D011743:Pyrimidines; C006253:pirinixic acid; D004051:Diethylhexyl Phthalate; D002118:Calcium