New Approach Methodologies - Systems Toxicology for understanding the effects of pulmonary surfactant corona formation on graphene oxide-based materials toxicity

• Grant number: 24/03881-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2025
• End date: February 29, 2028
• Field of knowledge: Interdisciplinary Subjects
• Principal Investigator: Diego Stéfani Teodoro Martinez
• Grantee: Matheus Alves Siqueira de Assunção
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

New Approach Methodologies (NAMs) are essential to support the safe and sustainable innovation in nanotechnology and advanced materials. Systems toxicology linked with adverse outcome pathways (AOPs) is providing a holistic and integrative approach to assessing molecular and functional changes occurring at different levels a biological system. The application of these approaches in nanosafety research represents the frontier of knowledge; however, it is still a scientifically underdeveloped area in the Brazilian context at this time. Success in translating these AOPs into nanosafety practices critically depends on exploring omics data and computational and informatics tools. In this project, we propose to develop a systems toxicology approach to assess the toxicity of graphene oxide-based materials, including leveraging strategic research connections with three leading international groups in the Europe (Birmingham, Manchester, and Tampere). Indeed, we are advancing to investigate the impact of pulmonary surfactant (PS) corona on graphene oxide-based materials (i.e., GO and GO-NH2) toxicity against lung cells (i.e., BEAS-2B) for the first time. The corona formation, secretomic assays, and biochemical functional assays will be characterized and analyzed concerning the identification of AOPs. GO reference material has been developed by INMETRO and will be studied in this project as a "model sample" toward harmonization practices linked to NAMs. Our preliminary results, showed that the synthetic PS corona can modulate cellular response to GO against BEAS-2B; and the protein component of PS had a greater impact on mitigating GO toxicity than the lipid component. Additionally, we demonstrated the possible induction of epithelial-mesenchymal transition (EMT) in the absence of proteins. Therefore, in this project, we aim to explain the different contributions of each PS component (proteins and lipids) in mitigating GO toxicity, investigating both GO-PS and GO-NH2-PS nanobiointeractions linked to their effects on cells. Finally, this project supports the development of predictive toxicity methods for graphene-based materials towards a safe-by-design, sustainable innovation, and regulation.