Translatability and transferability of in silico models: Context of use switching to predict the effects of environmental chemicals on the immune system

Pappalardo, Francesco; Russo, Giulia; Corsini, Emanuela; Paini, Alicia; Worth, Andrew

doi:10.1016/j.csbj.2022.03.024

Cited by 17 publications

(6 citation statements)

References 90 publications

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“…Promising examples are the use of mechanistic computational platforms, such as the Universal Immune System Simulator, UISS-TOX as described by Pappalardo and co-workers and in vitro high throughput platforms (as described by Naidenko et al [ 197 ]. Assumptions for the immunotoxicity mode of action of PFAS had to be taken by Pappalardo and co-workers for the UISS-TOX platform [ 198 ] that might not be fully supported by currently available data. Furthermore, PFAS show the limitations of the currently available high-throughput assays for immunotoxicity screening in the U.S. EPA ToxCast Program, as Naidenko and co-workers point out.…”

Section: Discussionmentioning

confidence: 99%

Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS)

et al. 2023

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Background Per- and polyfluoroalkyl substances (PFAS) are of public health concern, because of their ubiquitous and extremely persistent occurrence, and depending on their structure, their bio-accumulative, mobile and toxic properties. Human health effects associated with exposure to PFAS include adverse effects on the immune system. In 2020, EFSA (the European Food Safety Authority) defined adverse effects on the immune system as the most critical effect for human health risk assessment, based on reduced antibody responses to childhood vaccines and similar effects observed in experimental animal studies. Likewise, the U.S. EPA (Environmental Protection Agency) considers PFAS-induced immunotoxicity, especially in children, as the critical effect for risk assessment. However, the mechanisms by which antibody concentrations are impacted are not completely understood. Furthermore, other targets of the immune system functions have been reported in the literature. Objective The aim of this review is to explore PFAS-associated immune-related effects. This includes, relevant mechanisms that may underlie the observed effects on the immune system, immunosuppression as well as immunoenhancement, such as i) modulation of cell signalling and nuclear receptors, such as NF-κB and PPARs; ii) alteration of calcium signalling and homoeostasis in immune cells; iii) modulation of immune cell populations; iv) oxidative stress and v) impact on fatty acid metabolism & secondary effects on the immune system. Methods A literature research was conducted using three databases (Web of Science, PubMed, and Scopus), which were searched in July 2021 for relevant studies published in the time frame from 2018 to 2021. In total, 487 publications were identified as potentially eligible and following expert-based judgement, articles relevant for mechanisms of PFAS induced immunotoxicity are discussed. Conclusions Taken together, we show that there is substantial evidence from both in vitro and in vivo experimental as well as epidemiological studies, supporting that various PFAS, not only PFOA and PFOS, affect multiple aspects of the immune system. Timing of exposure is critical, because the developing immune system is especially vulnerable to toxic insults, resulting in a higher risk of particularly adverse immune effects but also other organs later in life.

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Section: Discussionmentioning

confidence: 99%

Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS)

et al. 2023

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“…In addition, Russo et al proposed a method for predicting ACD induced by skin sensitizers, using Universal Immune System Simulator (UISS), a state-of-the-art computational framework that can fully simulate the dynamic immune system [24]. It has also been shown to mimic the effects of the environmental immunotoxic substances PFAS on the immune system [103]. However, in contrast to skin sensitization, immunosuppression has no clear indicators or ways to determine its presence, which makes the selection of toxicity data very difficult.…”

Section: Development Of In Silico Methodsmentioning

confidence: 99%

Immunotoxicity In Vitro Assays for Environmental Pollutants under Paradigm Shift in Toxicity Tests

Wang

et al. 2022

IJERPH

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With the outbreak of COVID-19, increasingly more attention has been paid to the effects of environmental factors on the immune system of organisms, because environmental pollutants may act in synergy with viruses by affecting the immunity of organisms. The immune system is a developing defense system formed by all metazoans in the course of struggling with various internal and external factors, whose damage may lead to increased susceptibility to pathogens and diseases. Due to a greater vulnerability of the immune system, immunotoxicity has the potential to be the early event of other toxic effects, and should be incorporated into environmental risk assessment. However, compared with other toxicity endpoints, e.g., genotoxicity, endocrine toxicity, or developmental toxicity, there are many challenges for the immunotoxicity test of environmental pollutants; this is due to the lack of detailed mechanisms of action and reliable assay methods. In addition, with the strong appeal for animal-free experiments, there has been a significant shift in the toxicity test paradigm, from traditional animal experiments to high-throughput in vitro assays that rely on cell lines. Therefore, there is an urgent need to build high-though put immunotoxicity test methods to screen massive environmental pollutants. This paper reviews the common methods of immunotoxicity assays, including assays for direct immunotoxicity and skin sensitization. Direct immunotoxicity mainly refers to immunosuppression, for which the assays mostly use mixed immune cells or isolated single cells from animals with obvious problems, such as high cost, complex experimental operation, strong variability and so on. Meanwhile, there have been no stable and standard cell lines targeting immune functions developed for high-throughput tests. Compared with direct immunotoxicity, skin sensitizer screening has developed relatively mature in vitro assay methods based on an adverse outcome pathway (AOP), which points out the way forward for the paradigm shift in toxicity tests. According to the experience of skin sensitizer screening, this paper proposes that we also should seek appropriate nodes and establish more complete AOPs for immunosuppression and other immune-mediated diseases. Then, effective in vitro immunotoxicity assay methods can be developed targeting key events, simultaneously coordinating the studies of the chemical immunotoxicity mechanism, and further promoting the paradigm shift in the immunotoxicity test.

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“…Two decades ago, perfluorooctane sulfonate (PFOS) was found for the first time in the blood of wild animals and even in human blood [ 5 , 6 ]. Studies have shown that long-chain PFASs are potentially toxic and may cause reproductive and developmental defects, hepatotoxicity, neurotoxicity, and immunotoxicity [ 7 , 8 ]. In 2009, PFOS, its salts, and its precursor perfluorooctane sulfonyl fluoride (PFOSF) were restricted globally [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Analysis of the Bindings between Legacy and Novel Per- and Polyfluoroalkyl Substances and Human Serum Albumin

Wu,

Bao,

Liu

et al. 2024

Toxics

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Per- and polyfluoroalkyl substances (PFASs) are emerging contaminants of concern that can enter the human body through a variety of pathways and thereby cause harmful effects. Exposure of pregnant women to PFASs could even affect both the mother and the child. Human serum albumin (HSA) is considered to be the primary transport protein for a variety of substances in body fluids. It can be bound to different contaminants and might result in possible effects on human health. Yet, few studies are available on the binding affinity of legacy PFASs and their novel alternatives to HSA. In this study, the binding mechanisms of HSA to both legacy PFASs and their novel alternatives were investigated using fluorescence spectroscopy, together with further molecular docking. The results show that all the target PFASs were statically quenched against HSA with binding ratios of 1:1. The binding constants of long-chain PFASs and novel alternatives of perfluoroalkanesulfonic acids (PFSAs) were greater than 102, whereas those of short-chain PFASs alternatives and novel alternatives of perfluorocarboxylic acids (PFCAs) were less than 102. In general, the binding affinities of PFCAs on HSA were less than that of PFSAs, while the binding affinities of short-chain PFASs alternatives on HSA were smaller than those of long-chain PFASs and their novel alternatives. Therefore, bindings to HSA could be considered as an important influencing factor for the bioaccumulation of legacy and novel PFASs in the human body.

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Translatability and transferability of in silico models: Context of use switching to predict the effects of environmental chemicals on the immune system

Cited by 17 publications

References 90 publications

Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS)

Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS)

Immunotoxicity In Vitro Assays for Environmental Pollutants under Paradigm Shift in Toxicity Tests

In Vitro and In Silico Analysis of the Bindings between Legacy and Novel Per- and Polyfluoroalkyl Substances and Human Serum Albumin

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