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

Abstract

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.

Association between a Mixture of Per- and Polyfluoroalkyl Substances (PFAS) and Inflammatory Biomarkers in the Atlanta African American Maternal–Child Cohort

“…58 However, the exact mechanisms remain largely unclear. 57 Additional research is needed for further investigation into the various pathways and mechanisms through which PFAS exposure alters the levels of pro-inflammatory and anti-inflammatory cytokines during pregnancy.…”

“…PFOS can increase the formation of reactive oxygen species and lipid peroxidation in lymphocytes, and thus anti-inflammatory markers like IL-10 may be upregulated in response to an increase in oxidative stress. Additionally, PFAS can activate peroxisome proliferator-activated receptor gamma (PPARγ) expressed by osteoblasts, , which have the capacity to activate T-cell responses and modulate T-cell activation and thus produce anti-inflammatory cytokines, including IL-10 . However, the exact mechanisms remain largely unclear .…”

“…Additionally, PFAS can activate peroxisome proliferator-activated receptor gamma (PPARγ) expressed by osteoblasts, , which have the capacity to activate T-cell responses and modulate T-cell activation and thus produce anti-inflammatory cytokines, including IL-10 . However, the exact mechanisms remain largely unclear . Additional research is needed for further investigation into the various pathways and mechanisms through which PFAS exposure alters the levels of pro-inflammatory and anti-inflammatory cytokines during pregnancy.…”

Poly- and Perfluoroalkyl Substances Induce Immunotoxicity via the TLR Pathway in Zebrafish: Links to Carbon Chain Length

“…60 Almost eight kinds of PFASs have been found to have varying degrees of NF-κB activation in different animal models. 61 A plausible mechanism here is that PFBA, PFOA, and PFNA activate the TLR/MyD88/NF-κB pathway and subsequently cause disturbances in inflammatory responses. However, it should be noted that neither MyD88-MO nor MyD88 inhibitors can completely eliminate the immunotoxicity of PFASs.…”

“…The NF-κB pathway has long been considered a typical pro-inflammatory pathway based on its role in pro-inflammatory genes of cytokines, chemokines, and adhesion molecules expression . Almost eight kinds of PFASs have been found to have varying degrees of NF-κB activation in different animal models . A plausible mechanism here is that PFBA, PFOA, and PFNA activate the TLR/MyD88/NF-κB pathway and subsequently cause disturbances in inflammatory responses.…”