Assessment of acute and chronic toxicity of the heart and brain exposed to pesticides found in potable water in Brazil

• Grant number: 21/05584-7
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: September 01, 2022
• End date: August 31, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Toxicology
• Principal Investigator: Danilo Roman Campos
• Grantee: Danilo Roman Campos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Adriano de Jesus da Silva ; DANIELLE OLIVEIRA COSTA SANTOS ; Dr Udo Kraushaar ; Fernando Augusto de Oliveira Ribeiro ; João Bosco Pesquero ; Marcela Sorelli Carneiro Ramos ; Zhiguang Yuchi
• Associated research grant: 14/09861-1 - The role of late sodium current in the inherited and acquired cardiac arrhythmias: from the biophysics properties to new therapeutic targets, AP.JP
• Associated scholarship(s): 24/10785-0 - Evaluation of Wistar rat cardiotoxicity caused by subchronic oral exposure to the pyrethroid cypermethrin, BP.IC; 23/14219-6 - Evaluation of the cardiotoxicity of the fungicide Fluconazole, BP.DR; 22/14133-1 - Molecular mechanisms of increased susceptibility to cardiac arrhythmias due to chronic in vivo exposure to low doses of triazole pesticides: implications for worsening heart disease caused by Pulmonary Hypertension, BP.PD; + associated scholarships 23/11912-2 - Pesticide as an enhancement factor for Doxorubicin-induced cardiotoxicity, BP.PD; 23/04603-3 - Evaluation of in vivo cardiotoxicity of oral exposure to the triazol tebuconazole and the pyrethroid Bifenthrin, BP.DR; 23/04028-9 - Morphofunctional studies of cardiotoxicity induced by the pesticide chlorpyrifos, BP.IC; 21/15122-0 - CARDIOTOXICITY INDUCED BY THE PESTICIDE TEBUCONAZOLE IN MICE: FROM CONCEPTION TO ADULT LIFE, BP.DR; 22/07256-0 - Role of SCN5A polymorphisms on pharmacological properties of pesticides against Nav1.5, BP.PD - associated scholarships

Abstract

Brazil is the third country in the world in total tons of pesticides use per year. Pesticides are toxic substances or a mixture of substances that are naturally or chemically synthesized. They are widely used in agriculture to control plagues; however, since they are toxic to life, they are inevitably toxic to humans. Heavy use of pesticides has contaminated ecosystems. In Brazil, at least 27 pesticides are found in potable water, with a range of concentrations. Ministry of Health set concentration threshold levels for each pesticide, in theory not toxic, allowed to be found in potable water. However, in the literature, there is no systematic investigation of heart and nervous system toxicity of human tissue by these compounds at concentrations set by Ministry of Health. Also, there is no information if a mixture of these pesticides potentiates toxicity. Thus, to address these questions, we had the following aims: 1) evaluate in vitro single or mixture of pesticides in acute and chronic toxicity for cardiomyocytes and neurons derived from human-induced pluripotent stem cells, using the concentration approved by the Ministry of Health; 2) using mice determine in vivo if long-term low dose of single or a mixture of pesticides impact the functioning of the heart and central nervous system; 3) investigate in vivo how long-term low-dose pesticides impact the functioning of the heart and central nervous system in offspring of pregnant mice exposed to pesticides during pregnancy; 4) if SCN5A polymorphisms enhance the potency and toxicity of pesticides in vitro. At the end we will be able to determine the safety of potable water of Brazil in terms of pesticide contamination or if changes are needed in the guidelines of Ministry of Health. (AU)

Scientific publications

(16)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOUZA, DIEGO SANTOS; MARQUES, LEISIANE PEREIRA; COSTA, ALEXANDRE DANTAS; CRUZ, JADER SANTOS; RHANA, PAULA; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE VASCONCELOS; DURCO, AIMEE OBOLARI; LINS VASCONCELOS, CARLA MARIA; ROMAN-CAMPOS, DANILO. Experimental hypothyroidism induces cardiac arrhythmias and ranolazine reverts and prevents the phenotype. Life Sciences, v. 308, p. 13-pg., 2022-09-13. (20/14635-1, 21/05584-7, 19/21304-4, 19/18918-0)

TEIXEIRA-FONSECA, JORGE LUCAS; SANTOS-MIRANDA, ARTUR; MARQUES, IVAN LOBO SOUSA; MARQUES, LEISIANE PEREIRA; ALCANTARA, FABIANA; CONCEICAO, MICHAEL RAMON DE LIMA; SOUZA, DIEGO SANTOS; GONDIM, ANTONIO NEI SANTANA; ROMAN-CAMPOS, DANILO. Eugenol delays the onset of ouabain-induced ventricular cardiac arrhythmias in guinea pigs. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. N/A, p. 11-pg., 2023-09-19. (21/15122-0, 20/14635-1, 21/05584-7, 19/18918-0)

SOUZA, DIEGO SANTOS; ROMAN-CAMPOS, DANILO. Cardiotoxicity and triazole pesticides: therapeutic options for a neglected heart disease. EXPERT REVIEW OF CARDIOVASCULAR THERAPY, v. 23, n. 3, p. 3-pg., 2025-03-09. (21/05584-7)

JORGE LUCAS TEIXEIRA-FONSECA; DIEGO JOSE BELATO Y ORTS; POLYANA LEAL DA SILVA; MICHAEL RAMON DE LIMA CONCEIÇÃO; HERNAN HERMES; CARLOS R. PRUDENCIO; DANILO ROMAN-CAMPOS. Atividade Anti-Inflamatória In Vivo do D-Limoneno em um Modelo de Hipertensão Pulmonar Induzida por Monocrotalina em Ratos: Implicações à Função Cardíaca. Arquivos Brasileiros de Cardiologia, v. 121, n. 12, 2024-12-13. (21/05584-7, 22/14133-1, 20/14635-1, 22/07256-0)

CONCEICAO, MICHAEL RAMON DE LIMA; TEIXEIRA-FONSECA, JORGE LUCAS; ORTS, DIEGO JOSE BELATO; NASCIMENTO, DANIELLA SANTOS; DANTAS, CACIA OLIVEIRA; DE VASCONCELOS, CARLA MARIA LINS; SOUZA, DIEGO SANTOS; ROMAN-CAMPOS, DANILO. Exploring the interplay between extracellular pH and Dronedarone's pharmacological effects on cardiac function. European Journal of Pharmacology, v. 983, p. 11-pg., 2024-09-12. (24/06444-2, 22/07256-0, 22/14133-1, 21/05584-7, 20/14635-1)

DURCO, AIMEE OBOLARI; SOUZA, DIEGO SANTOS; CONCEICAO, MICHAEL RAMON DE LIMA; BESERRA, SAMUEL DOS SANTOS; DA FONSECA, JORGE LUCAS TEIXEIRA; LOCH, LEONARDO; SILVA, MICHEL AUGUSTO; DE OLIVEIRA, ALDEIDIA PEREIRA; ARAUJO, ADRIANO ANTUNES DE SOUZA; DE VASCONCELOS, CARLA MARIA LINS; et al. D-limonene complexed with hydroxypropyl-(3-cyclodextrin prevents impaired cardiac excitation-contraction coupling by reducing oxidative stress and cardiac apoptosis in an animal model of cardiotoxicity induced by doxorubicin. Chemico-Biological Interactions, v. 418, p. 10-pg., 2025-09-05. (21/05584-7, 23/11912-2, 22/14133-1, 24/06444-2, 20/14635-1, 09/53840-0)

TEIXEIRA-FONSECA, JORGE LUCAS; BELATO Y ORTS, DIEGO JOSE; DA SILVA, POLYANA LEAL; CONCEICAO, MICHAEL RAMON DE LIMA; HERMES, HERNAN; PRUDENCIO, CARLOS R.; ROMAN-CAMPOS, DANILO. In Vivo Anti-Inflammatory Activity of D-Limonene in a Rat Model of Monocrotaline-Induced Pulmonary Hypertension: Implications to the. Arquivos Brasileiros de Cardiologia, v. 121, n. 12, p. 11-pg., 2024-01-01. (21/05584-7, 22/07256-0, 20/14635-1)

MARQUES, LEISIANE P.; JOVIANO-SANTOS, JULLIANE, V; SOUZA, DIEGO S.; SANTOS-MIRANDA, A.; ROMAN-CAMPOS, D.. Cardiotoxicity of pyrethroids: molecular mechanisms and therapeutic options for acute and long-term toxicity. BIOCHEMICAL SOCIETY TRANSACTIONS, v. N/A, p. 15-pg., 2022-10-31. (21/15122-0, 21/05584-7, 19/18918-0)

JORGE LUCAS TEIXEIRA-FONSECA; JULLIANE VASCONCELOS JOVIANO-SANTOS; FABIANA DA SILVA ALCÂNTARA; POLYANA LEAL DA SILVA; MICHAEL RAMON LIMA CONCEIÇÃO; DANILO ROMAN-CAMPOS. Estudo Morfofuncional do Átrio Esquerdo Isolado de um Modelo Experimental de Hipertensão Pulmonar em Ratos. Arquivos Brasileiros de Cardiologia, v. 120, n. 10, 2023-10-20. (21/05584-7, 19/21304-4)

TEIXEIRA-FONSECA, JORGE LUCAS; SOUZA, DIEGO SANTOS; CONCEICAO, MICHAEL RAMON DE LIMA; MARQUES, LEISIANE PEREIRA; DURCO, AIMEE OBOLARI; DA SILVA, POLYANA LEAL; JOVIANO-SANTOS, JULLIANE V.; SANTOS-MIRANDA, ARTUR; ROMAN-CAMPOS, DANILO. In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species. Food and Chemical Toxicology, v. 187, p. 12-pg., 2024-04-04. (22/14133-1, 21/05584-7, 20/14635-1, 21/15122-0, 23/11912-2)

DE CONCEICAO, MICHAEL RAMON LIMA; TEIXEIRA-FONSECA, JORGE LUCAS; MARQUES, LEISIANE PEREIRA; SOUZA, DIEGO SANTOS; ROMAN-CAMPOS, DANILO. Interaction of the antiarrhythmic drug Amiodarone with the sodium channel Nav1.5 depends on the extracellular pH. European Journal of Pharmacology, v. 960, p. 12-pg., 2023-10-24. (21/05584-7, 19/18918-0, 21/15122-0, 20/14635-1)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, V. JULLIANE; CRUZ-NASCIMENTO, TAYNARA; NERI, ELIDA ADALGISA; SOUZA, DIEGO SANTOS; MARQUES, LEISIANE PEREIRA; KRIEGER, JOSE E.; ROMAN-CAMPOS, DANILO. The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells. Toxicology Letters, v. 359, p. 10-pg., 2022-04-15. (18/22830-9, 19/18918-0, 21/05584-7, 19/21304-4, 20/14635-1, 18/20777-3)

MARQUES, LEISIANE PEREIRA; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE VASCONCELOS; TEIXEIRA-FONSECA, JORGE LUCAS; ALCANTARA, FABIANA DA SILVA; SARMENTO, JAQUELINE OLIVEIRA; ROMAN-CAMPOS, DANILO. The fungicide tebuconazole modulates the sodium current of human Na_V1.5 channels expressed in HEK293 cells. Food and Chemical Toxicology, v. 180, p. 12-pg., 2023-08-30. (21/15122-0, 20/14635-1, 21/05584-7)

TEIXEIRA-FONSECA, JORGE LUCAS; DE LIMA CONCEICAO, MICHAEL RAMON; LEAL-SILVA, POLYANA; ROMAN-CAMPOS, DANILO. Ranolazine exerts atrial antiarrhythmic effects in a rat model of monocrotaline-induced pulmonary hypertension. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. 132, n. 5, p. 10-pg., 2023-03-01. (19/21304-4, 21/05584-7)

DA SILVA, MARIA VITORIA; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE, V; SOUZA, DIEGO SANTOS; MARQUES, LEISIANE PEREIRA; SARMENTO, JAQUELINE OLIVEIRA; BESERRA, SAMUEL SANTOS; ROMAN-CAMPOS, DANILO. The insecticide beta-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype. Clinical Science, v. 136, n. 5, p. 15-pg., 2022-03-01. (21/05584-7, 19/18918-0, 18/20777-3, 18/22830-9, 20/09403-4, 19/21304-4)

TEIXEIRA-FONSECA, JORGE LUCAS; JOVIANO-SANTOS, JULLIANE V.; BESERRA, SAMUEL SANTOS; CONCEICAO, MICHAEL RAMON DE LIMA; LEAL-SILVA, POLYANA; MARQUES, LEISIANE PEREIRA; SOUZA, DIEGO SANTOS; ROMAN-CAMPOS, DANILO. Exploring the involvement of TASK-1 in the control of isolated rat right atrium function from healthy animals and an experimental model of monocrotaline-induced pulmonary hypertension. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. N/A, p. 14-pg., 2023-06-20. (19/21304-4, 19/18918-0, 21/15122-0, 20/14635-1, 21/05584-7)