Abstract
Background: Non-communicable diseases, intended as the results of a combination of inherited, environmental and biological factors, kill 40 million people each year, equivalent to roughly 70% of all premature deaths globally. The possibility that manufactured nanoparticles (NPs) may affect cardiac performance, has led to recognize NPs-exposure not only as a major Public Health concern, but also as an occupational hazard. In volunteers, NPs-exposure is problematic to quantify. We recently found that inhaled titanium dioxide NPs, one of the most produced engineered nanomaterials, acutely increased cardiac excitability and promoted arrhythmogenesis in normotensive rats by a direct interaction with cardiac cells. We hypothesized that such scenario can be exacerbated by latent cardiovascular disorders such as hypertension. Results: We monitored cardiac electromechanical performance in spontaneously hypertensive rats (SHRs) exposed to titanium dioxide NPs for 6 weeks using a combination of cardiac functional measurements associated with toxicological, immunological, physical and genetic assays. Longitudinal radio-telemetry ECG recordings and multiple-lead epicardial potential mapping revealed that atrial activation times significantly increased as well as proneness to arrhythmia. At the third week of nanoparticles administration, the lung and cardiac tissue encountered a maladaptive irreversible structural remodelling starting with increased pro-inflammatory cytokines levels and lipid peroxidation, resulting in upregulation of the main pro-fibrotic cardiac genes. At the end of the exposure, the majority of spontaneous arrhythmic events terminated, while cardiac hemodynamic deteriorated and a significant accumulation of fibrotic tissue occurred as compared to control untreated SHRs. Titanium dioxide nanoparticles were quantified in the heart tissue although without definite accumulation as revealed by particle-induced X-ray emission and ultrastructural analysis. Conclusions: The co-morbidity of hypertension and inhaled nanoparticles induces irreversible hemodynamic impairment associated with cardiac structural damage potentially leading to heart failure. The time-dependence of exposure indicates a non-return point that needs to be taken into account in hypertensive subjects daily exposed to nanoparticles.
Original language | English |
---|---|
Article number | 25 |
Pages (from-to) | 25 |
Journal | Particle and Fibre Toxicology |
Volume | 16 |
Issue number | 1 |
DOIs | |
Publication status | Published - 24 Jun 2019 |
Funding
Experiments were conducted on sixty-four 12-week-old Spontaneously Hypertensive male rats (Envigo, Huntingdon, United Kingdom, SHR, Harlan Laboratories s.r.l., Italy) singly housed with the light on between 7 a.m. and 7 p.m. in a temperature-controlled room at 22–24 °C. The bedding of the cages consisted of wood shavings with food and water available ad libitum. All surgery procedures and experiments, when specified, were performed under anesthesia which consisted of a mixture of ketamine chloride (40 mg/kg ip; Imalgene, Merial, Milano, Italy) and medetomidine hydrochloride (0.15 mg/ kg ip; Domitor, Pfizer Italia s.r.l., Latina, Italy). The period of study was selected by taking into consideration the frailty of SHR animals and their suffering due to the hypertensive condition. This study was carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health (Bethesda, MD, USA, revised 1996). The protocol was approved by the Veterinary Animal Care and Use Committee of the University of Parma (Permit: n. PMS 53/2009) and conforms to the National Ethical Guidelines of the Italian Ministry of Health. All effort was made to minimize suffering. We noticed 15% of spontaneous animal loss during the repeated anesthesia procedures from the 3rd week onwards because of the SHR hyperreactivity [38]. We did not observe animal loss for the surgical procedure. Italian Ministry of Health young research grant GR-2009-1530528 to Mi.Mi, A.M. FP7-Quality Nano Research and Infrastructure Project FUNDP-TAF-225, FP7 to Mi.Mi., L.G., and to O.L.G. Italian Ministry of Health, Ricerca Finalizzata grant NanOI-LuCaS RF-2009-1472550 to A.M. Department of Innovation, Research and Universities of the Autonomous Province of Bolzano-South Tyrol (Italy) to L.G., A.P., V.M, A.R. Fondo Guido Erluison per la Ricerca Clinica, Dipartimento di Medicina e Chirurgia postdoctorate salary to S.R. CSEIA 2018 Open-Up - Outgoing Publications grant for scientific publication to S.R. The protocol was approved by the Veterinary Animal Care and Use Committee of the University of Parma (Permit: n. PMS 53/2009) and conforms to the National Ethical Guidelines of the Italian Ministry of Health.
Keywords
- Arrhythmias
- Cardiac electrophysiology
- Cardiac fibrosis
- Nanotoxicology
- Titanium dioxide nanoparticles
- Rats, Inbred SHR
- Hypertension/pathology
- Ventricular Function, Left
- Nanoparticles/toxicity
- Telemetry
- Dose-Response Relationship, Drug
- Titanium/toxicity
- Animals
- Heart/drug effects
- Blood Pressure/drug effects
- Myocardium/pathology
- Heart Rate/drug effects
- Fibrosis
- Electrocardiography
Fingerprint
Dive into the research topics of 'Subchronic exposure to titanium dioxide nanoparticles modifies cardiac structure and performance in spontaneously hypertensive rats'. Together they form a unique fingerprint.Datasets
-
Additional file 1: of Subchronic exposure to titanium dioxide nanoparticles modifies cardiac structure and performance in spontaneously hypertensive rats
Rossi, S. (Creator), Savi, M. (Creator), Mazzola, M. (Creator), Pinelli, S. (Creator), Alinovi, R. (Creator), Gennaccaro, L. (Contributor), Pagliaro, A. (Creator), Meraviglia, V. (Creator), Galetti, M. (Creator), Lozano-Garcia, O. (Contributor), Rossini, A. (Creator), Frati, C. (Creator), Falco, A. (Creator), Quaini, F. (Creator), Bocchi, L. (Creator), Stilli, D. (Creator), Lucas, S. (Contributor), Goldoni, M. (Creator), Macchi, E. (Creator), Mutti, A. (Creator) & Miragoli, M. (Creator), University of Namur, 24 Jun 2019
DOI: 10.6084/m9.figshare.8318558.v1, https://springernature.figshare.com/articles/Additional_file_1_of_Subchronic_exposure_to_titanium_dioxide_nanoparticles_modifies_cardiac_structure_and_performance_in_spontaneously_hypertensive_rats/8318558/1
Dataset
-
Subchronic exposure to titanium dioxide nanoparticles modifies cardiac structure and performance in spontaneously hypertensive rats
Rossi, S. (Creator), Savi, M. (Creator), Mazzola, M. (Creator), Pinelli, S. (Creator), Alinovi, R. (Creator), Gennaccaro, L. (Contributor), Pagliaro, A. (Creator), Meraviglia, V. (Creator), Galetti, M. (Creator), Lozano-Garcia, O. (Contributor), Rossini, A. (Creator), Frati, C. (Creator), Falco, A. (Creator), Quaini, F. (Creator), Bocchi, L. (Creator), Stilli, D. (Creator), Lucas, S. (Contributor), Goldoni, M. (Creator), Macchi, E. (Creator), Mutti, A. (Creator) & Miragoli, M. (Creator), University of Namur, 24 Jun 2019
DOI: 10.6084/m9.figshare.c.4553603.v1, https://springernature.figshare.com/collections/Subchronic_exposure_to_titanium_dioxide_nanoparticles_modifies_cardiac_structure_and_performance_in_spontaneously_hypertensive_rats/4553603/1
Dataset
-
Additional file 4: of Subchronic exposure to titanium dioxide nanoparticles modifies cardiac structure and performance in spontaneously hypertensive rats
Rossi, S. (Creator), Savi, M. (Creator), Mazzola, M. (Creator), Pinelli, S. (Creator), Alinovi, R. (Creator), Gennaccaro, L. (Contributor), Pagliaro, A. (Creator), Meraviglia, V. (Creator), Galetti, M. (Creator), Lozano-Garcia, O. (Contributor), Rossini, A. (Creator), Frati, C. (Creator), Falco, A. (Creator), Quaini, F. (Creator), Bocchi, L. (Creator), Stilli, D. (Creator), Lucas, S. (Contributor), Goldoni, M. (Creator), Macchi, E. (Creator), Mutti, A. (Creator) & Miragoli, M. (Creator), University of Namur, 24 Jun 2019
DOI: 10.6084/m9.figshare.8318582.v1, https://springernature.figshare.com/articles/Additional_file_4_of_Subchronic_exposure_to_titanium_dioxide_nanoparticles_modifies_cardiac_structure_and_performance_in_spontaneously_hypertensive_rats/8318582/1
Dataset