The effect of phthalates on the heart: molecular pathways and clinical relevance

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DESCRIPTION (provided by applicant): Di(2-ethylhexyl) phthalate (DEHP) is used in a variety of medical products, as it allows stiff plastics, such as polyvinyl chloride, to become more flexible. DEHP is commonly found in medical devices, including intravenous bags and tubing that are used for various procedures. DEHP is highly hydrophobic, and as a result, it leaches from plastics when in contact with blood, serum, and other lipophilic fluids. Since a number of animal studies have reported toxic effects of DEHP, phthalate leaching is a source of concern for human health. The majority of previous studies focused on DEHP carcinogenicity and its adverse effects on reproductive health. Indeed, the risk of testicular toxicity was found to be substantial enough to warrant the use of DEHP-free plastics for premature boys. In contrast, little is known about the adverse effects of DEHP on the heart, and awareness of its potential cardiotoxicity is essentially non-existent. When clinically relevant concentrations of DEHP were applied to monolayers of rat neonatal cardiomyocytes, treatment markedly impaired conduction velocity and diminished the amount of connexin-43. DEHP treatment also affected the adhesion and motion of the cell layers. The main goals of the proposed studies are to confirm and understand the mechanism behind DEHP's effect on cardiac muscle and to establish its clinical relevance. Aim 1 of the proposal is to dissect the molecular pathways affected by DEHP that leads to cardiac electrical uncoupling using genomics and computational strategies. Clinically relevant concentrations of DEHP will be delivered parenterally via implantable osmotic pumps. Ventricular cardiac tissue will be collected and modifications in gene expression will be assessed. Key candidate genes will be further investigated using functional validation assays. Aim 2 of the proposal is to determine if in vivo exposure to DEHP leads to cardiac dysfunction. DEHP will be delivered parenterally via implantable osmotic pumps. Echocardiography will be conducted to assess contractility in vivo, both before and after DEHP treatment. Optical mapping of excised hearts will measure changes in local conduction velocities, calcium transients and calcium handling.