Review

Authors: Nell Hirt, Mathilde Body-Malapel

BACKGROUND

Together with poor biodegradability and insufficient recycling, the massive production and use of plastics have led to widespread environmental contamination by nano- and microplastics. These particles accumulate across ecosystems - even in the most remote habitats - and are transferred through food chains, leading to inevitable human ingestion, that adds to the highest one due to food processes and packaging.

OBJECTIVE

The present review aimed at providing a comprehensive overview of current knowledge regarding the effects of nano- and microplastics on intestinal homeostasis.

METHODS

We conducted a literature search focused on the in vivo effects of nano- and microplastics on gut epithelium and microbiota, as well as on immune response.

RESULTS

Numerous animal studies have shown that exposure to nano- and microplastics leads to impairments in oxidative and inflammatory intestinal balance, and disruption of the gut's epithelial permeability. Other notable effects of nano- and microplastic exposure include dysbiosis (changes in the gut microbiota) and immune cell toxicity. Moreover, microplastics contain additives, adsorb contaminants, and may promote the growth of bacterial pathogens on their surfaces: they are potential carriers of intestinal toxicants and pathogens that can potentially lead to further adverse effects.

CONCLUSION

Despite the scarcity of reports directly relevant to human, this review brings together a growing body of evidence showing that nano- and microplastic exposure disturbs the gut microbiota and critical intestinal functions. Such effects may promote the development of chronic immune disorders. Further investigation of this threat to human health is warranted.

Topics: Animals; Gastrointestinal Microbiome; Humans; Immune System; Microplastics

PubMed: 33183327
DOI: 10.1186/s12989-020-00387-7

Review

Authors: Dongsheng Duan

High-dose systemic gene therapy with adeno-associated virus (AAV) is in clinical trials to treat various inherited diseases. Despite remarkable success in spinal muscular atrophy and promising results in other diseases, fatality has been observed due to liver, kidney, heart, or lung failure. Innate and adaptive immune responses to the vector play a critical role in the toxicity. Host factors also contribute to patient death. This mini-review summarizes clinical findings and calls for concerted efforts from all stakeholders to better understand the mechanisms underlying lethality in AAV gene therapy and to develop effective strategies to prevent/treat high-dose systemic AAV-gene-therapy-induced immunotoxicity.

Topics: Humans; Dystrophin; Dependovirus; Genetic Therapy; Immunity, Humoral; Muscular Dystrophy, Duchenne; Genetic Vectors

PubMed: 37822079
DOI: 10.1016/j.ymthe.2023.10.015

Review

Authors: Veronika Ehrlich, Wieneke Bil, Rob Vandebriel...

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.

Topics: Child; Animals; Humans; Fluorocarbons; Oxidative Stress; Public Health; Risk Assessment; Alkanesulfonic Acids; Environmental Pollutants

PubMed: 36814257
DOI: 10.1186/s12940-022-00958-5

Review

Authors: Andi Alijagic, Alexander Hedbrant, Alexander Persson...

Micro- and nanoplastics (MNPs) are emerging pollutants with scarcely investigated effects on human innate immunity. If they follow a similar course of action as other, more thoroughly investigated particulates, MNPs may penetrate epithelial barriers, potentially triggering a cascade of signaling events leading to cell damage and inflammation. Inflammasomes are intracellular multiprotein complexes and stimulus-induced sensors critical for mounting inflammatory responses upon recognition of pathogen- or damage-associated molecular patterns. Among these, the NLRP3 inflammasome is the most studied in terms of activation particulates. However, studies delineating the ability of MNPs to affect NLRP3 inflammasome activation are still rare. In this review, we address the issue of MNPs source and fate, highlight the main concepts of inflammasome activation particulates, and explore recent advances in using inflammasome activation for assessment of MNP immunotoxicity. We also discuss the impact of co-exposure and MNP complex chemistry in potential inflammasome activation. Development of robust biological sensors is crucial in order to maximize global efforts to effectively address and mitigate risks that MNPs pose for human health.

Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Microplastics; Immunity, Innate; Inflammation

PubMed: 37143682
DOI: 10.3389/fimmu.2023.1178434

Review

Authors: Yuhang Sun, Yuqi Song, Miao Long...

Aflatoxin B1 (AFB1), ochratoxin A (OTA), and deoxynivalenol (DON) are the three mycotoxins that have received the most scholarly attention and have been tested most routinely in clinics. These mycotoxins not only suppress immune responses but also induce inflammation and even increase susceptibility to pathogens. Here, we comprehensively reviewed the determining factors for the bidirectional immunotoxicity of the three mycotoxins, their effects on pathogens, and their action mechanisms. The determining factors include mycotoxin exposure doses and times, as well as species, sex, and some immunologic stimulants. Moreover, mycotoxin exposure can affect the infection severity of some pathogens, including bacteria, viruses, and parasites. Their specific action mechanisms include three aspects: (1) mycotoxin exposure directly promotes the proliferation of pathogenic microorganisms; (2) mycotoxins produce toxicity, destroy the integrity of the mucosal barrier, and promote inflammatory response, thereby improving the susceptibility of the host; (3) mycotoxins reduce the activity of some specific immune cells and induce immune suppression, resulting in reduced host resistance. The present review will provide a scientific basis for the control of these three mycotoxins and also provide a reference for research on the causes of increased subclinical infections.

Topics: Mycotoxins; Bacteria; Aflatoxin B1

PubMed: 36977078
DOI: 10.3390/toxins15030187

Review

Authors: Maroun Bou Zerdan, Sara Moussa, Ali Atoui...

The immune system defends the body against certain tumor cells and against foreign agents such as fungi, parasites, bacteria, and viruses. One of its main roles is to distinguish endogenous components from non-self-components. An unproperly functioning immune system is prone to primary immune deficiencies caused by either primary immune deficiencies such as genetic defects or secondary immune deficiencies such as physical, chemical, and in some instances, psychological stressors. In the manuscript, we will provide a brief overview of the immune system and immunotoxicology. We will also describe the biochemical mechanisms of immunotoxicants and how to evaluate immunotoxicity.

Topics: Allergens; Animals; Environmental Illness; Food Hypersensitivity; Humans; Intestinal Mucosa; Respiratory Hypersensitivity; Respiratory Mucosa

PubMed: 34361007
DOI: 10.3390/ijms22158242

Review

Authors: Xinge Wang, Na Li, Mei Ma...

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.

Topics: Animals; Environmental Pollutants; COVID-19; Toxicity Tests; Immune System; Risk Assessment

PubMed: 36612599
DOI: 10.3390/ijerph20010273

Authors: Jing Zhang, Zongming Ren, Meng Chen...

As a new alternative to perfluorooctane sulfonic acid (PFOS), 6:2 fluorotelomer sulfonic acid (6:2 FTSA) has been widely produced and used in recent years, and its concentration and frequency of detection in the aquatic environment and aquatic organisms are increasing. However, studies of its toxicity in aquatic biological systems are alarmingly scarce, and the relevant toxicological information needs to be improved. In this study, we investigated AB wild-type zebrafish () embryos subjected to acute 6:2 FTSA exposure for immunotoxicity using immunoassays and transcriptomics. Immune indexes showed significant decreases in SOD and LZM activities, but no significant change in NO content. Other indexes (TNOS, iNOS, ACP, AKP activities, and MDA, IL-1β, TNF-α, NF-κB, TLR4 content) all showed significant increases. These results indicated that 6:2 FTSA induced oxidative stress and inflammatory responses in zebrafish embryos and exhibited immunotoxicity. Consistently, transcriptomics showed that genes involved in the MAPK, TLR and NOD-like receptor signaling pathways (, , , , , , , and ) were significantly upregulated after 6:2 FTSA exposure, suggesting that 6:2 FTSA might induce immunotoxicity in zebrafish embryos through the TLR/NOD-MAPK pathway. The results of this study indicate that the safety of 6:2 FTSA should be examined further.

PubMed: 37235273
DOI: 10.3390/toxics11050459

Review

Authors: Jodi R Schilz, Erica J Dashner-Titus, Karen A Simmons...

Uranium is a naturally occurring element found in the environment as a mixture of isotopes with differing radioactive properties. Enrichment of mined material results in depleted uranium waste with substantially reduced radioactivity but retains the capacity for chemical toxicity. Uranium mine and milling waste are dispersed by wind and rain leading to environmental exposures through soil, air, and water contamination. Uranium exposure is associated with numerous adverse health outcomes in humans, yet there is limited understanding of the effects of depleted uranium on the immune system. The purpose of this review is to summarize findings on uranium immunotoxicity obtained from cell, rodent and human population studies. We also highlight how each model contributes to an understanding of mechanisms that lead to immunotoxicity and limitations inherent within each system. Information from population, animal, and laboratory studies will be needed to significantly expand our knowledge of the contributions of depleted uranium to immune dysregulation, which may then inform prevention or intervention measures for exposed communities.

Topics: Animals; Environmental Exposure; Humans; Mining; Soil; Uranium; Water

PubMed: 36152676
DOI: 10.1016/j.taap.2022.116252

Review

Authors: Wenjie Yang, Nahar Jannatun, Yanqiao Zeng...

Most disposable plastic products are degraded slowly in the natural environment and continually turned to microplastics (MPs) and nanoplastics (NPs), posing additional environmental hazards. The toxicological assessment of MPs for marine organisms and mammals has been reported. Thus, there is an urgent need to be aware of the harm of MPs to the human immune system and more studies about immunological assessments. This review focuses on how MPs are produced and how they may interact with the environment and our body, particularly their immune responses and immunotoxicity. MPs can be taken up by cells, thus disrupting the intracellular signaling pathways, altering the immune homeostasis and finally causing damage to tissues and organs. The generation of reactive oxygen species is the mainly toxicological mechanisms after MP exposure, which may further induce the production of danger-associated molecular patterns (DAMPs) and associate with the processes of toll-like receptors (TLRs) disruption, cytokine production, and inflammatory responses in immune cells. MPs effectively interact with cell membranes or intracellular proteins to form a protein-corona, and combine with external pollutants, chemicals, and pathogens to induce greater toxicity and strong adverse effects. A comprehensive research on the immunotoxicity effects and mechanisms of MPs, including various chemical compositions, shapes, sizes, combined exposure and concentrations, is worth to be studied. Therefore, it is urgently needed to further elucidate the immunological hazards and risks of humans that exposed to MPs.

PubMed: 36238600
DOI: 10.3389/ftox.2022.956885