Using NAMs to Address PFAS Immunotoxicity: an Integrated in Vitro and in Silico Testing Strategy to Study their Effects on Antibody Production

Università degli Studi di Milano Perfluorinated substances (PFAS) are a class of synthetic chemicals widely used in industry to which people and the environment are exposed. Human studies have shown that PFAS can cause immunosuppression, lower resistance to disease, and increase risk of infections with decreased response to vaccinations. However, not much is known about the mechanism of action of these substances. We evaluate the immunotoxic effects of PFAS and identify underlying mechanisms using new approach methodologies (NAMs). Our integrated testing strategy (ITS) developed both in vitro and in silico methods. Based on the in vivo evidence of reduced antibody production, suitable in vitro models were identified to evaluate the most relevant in vivo effect related to PFAS immunotoxicity. The effects of PFAS on the most important immune cells were studied using human models, and the results with the selected NAMs supported the in vivo evidence. Furthermore, mathematical fate and distribution models were used to identify nominal concentration of PFAS in the in vitro cell system and physiologically based kinetics model were used to perform quantitative in vitro to in vivo extrapolation. We used the "Universal Immune System Simulator" to complete the ITS and investigate the effects of PFAS on vulnerable populations and predict threshold doses with immune adverse outcomes. In agreement with the literature, the in silico results show differing immunosuppression for the four PFAS, supporting in vivo evidence of possible reduced resistance to infections due to impaired antibody response. The ITS provides a workflow for the use of alternative methods to study the dynamics and kinetics of PFAS and their physiological consequences. For more information see: https://doi.org/10.2903/sp.efsa.2024.EN-8926 https://doi.org/10.1016/j.csbj.2024.06.036 *Contents* 00:00 - Introduction 06:01 - Using NAMs to Address PFAS Immunotoxicity: an Integrated in Vitro and in Silico Testing Strategy to Study their Effects on Antibody Production 45:14 - Questions and Discussion For the slides in this talk, visit: https://drive.google.com/file/d/1qTWkSWFZvE-RcJFbtLU4P0Am8l0v8rMh/view?usp=sharing If you found this video useful, please check out our other videos on computational modeling, infection and immunology: https://youtube.com/playlist?list=PLiEtieOeWbMKh9VcQoinSwODcSZKMTGat Please consider joining our IMAG/MSM WG on Multiscale Modeling and Viral Pandemics: https://www.imagwiki.nibib.nih.gov/content/msm-viral-pandemics-meetings Please also consider joining the Global Alliance for Immune Prediction and Intervention: http://glimprint.org/