Per- and polyfluoroalkyl substances alter innate immune function: evidence and data gaps

Abstract

Per- and polyfluoroalkyl substances (PFASs) are a large class of compounds used in a variety of processes and consumer products. Their unique chemical properties make them ubiquitous and persistent environmental contaminants while also making them economically viable and socially convenient. To date, several reviews have been published to synthesize information regarding the immunotoxic effects of PFASs on the adaptive immune system. However, these reviews often do not include data on the impact of these compounds on innate immunity. Here, current literature is reviewed to identify and incorporate data regarding the effects of PFASs on innate immunity in humans, experimental models, and wildlife. Known mechanisms by which PFASs modulate innate immune function are also reviewed, including disruption of cell signaling, metabolism, and tissue-level effects. For PFASs where innate immune data are available, results are equivocal, raising additional questions about common mechanisms or pathways of toxicity, but highlighting that the innate immune system within several species can be perturbed by exposure to PFASs. Recommendations are provided for future research to inform hazard identification, risk assessment, and risk management practices for PFASs to protect the immune systems of exposed organisms as well as environmental health.

Keywords: PFAS; Per- and polyfluoroalkyl substances; ecotoxicology; immunotoxicology; innate immunity; zebrafish.

Figure 1.. Chemical structures of PFASs discussed in this review.

Structures were made using ChemDraw Professional (v16.0.1.4) and standard International Union of Pure and Applied Chemistry (IUPAC) nomenclature. Structures are organized according to a previously described scheme (Wang et al. 2017).

Figure 2.. Visual summary of mechanisms of PFAS toxicity observed in monocytes, microglia, and macrophages.

PFASs have been shown to disrupt immune signaling and other pathways in (A) monocytes (Corsini et al. 2011, 2012, 2021; Racchi et al. 2017; Masi et al. 2022), (B) microglia (Yang et al. 2015; Wang et al. 2015; Zhu et al. 2015; Ge et al. 2016; Lin et al. 2022), and (C) macrophages (Chang et al. 2005; Miyano et al. 2012; Kong et al. 2019; Wang [L] et al. 2021; Tian et al. 2021; Yu et al. 2022; Lee et al. 2022; Wang [D] et al. 2023). Black arrows and red lines with a “T” end indicate normal function (activating and inhibiting, respectively). PFAS-induced endpoints for each gene/protein are shown graphically as red up arrows (increase in signal and/or expression), blue down arrows (decrease in signal/expression), dash (no observed change), checkmark (binding between protein and any PFAS observed in vitro), checkmark with question mark (binding between protein and any PFAS suggested in silico, but not demonstrated in vitro). Details are provided in Supplementary Table 1. Abbreviations: AIM2: absent in melanoma 2; Arg-1: Arginase 1; ASC: Apoptosis-associated speck-like protein containing a CARD; BAK: Bcl-2 homologous antagonist killer; BAX: Bcl-2-associated X protein; BCL-2: B-cell lymphoma 2; BIP: Binding immunoglobulin protein; Casp1: Caspase 1; Casp3: Caspase 3; CCL2: Chemokine ligand 2, also called MCP-1; CXCL1: Chemokine (CXC motif) ligand 1; CD: Cluster of Differentiation (multiple types); COX2: Cytochrome c oxidase II; Cyt C: Cytochrome C; ERK: Extracellular signal-regulated kinase; H2-Aa: Histocompatibility 2, Class II antigen A, alpha; H2-K1: histocompatibility 2, K1, K region; IFNγ: Interferon-γ; IκB: nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor; IL: Interleukin (several types); iNOS: Inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; KO: knockout; LPS: Lipopoly-saccharide; MAPK: Mitogen-activated protein kinase; MMP9: Matrix metallopeptidase- 9; mtDNA: Mitochondrial DNA; NF-κB: Nuclear factor κ-light-chain-enhancer of activated B- cells; NLRP3: NOD-like receptor family pyrin domain containing 3; OPN: Osteopontin; PARP: Poly (ADP-ribose) polymerase; PGE-2: Prostaglandin E₂; PI3K: Phosphoinositide 3-kinase; PKCβ: Protein kinase Cβ; PPARα: Peroxisome proliferator-activated receptor-α; RACK1: Receptor for activated C kinase 1; RCS: Reactive carbonyl species; ROS: Reactive oxygen species; STAT3: Signal transducer and activator of transcription-3; TNFα: Tumor necrosis factor-α.

Figure 3.. Visual summary of mechanisms suggested in tissue-level, acellular, and other studies not specifically in innate immune cells.

PFAS have been shown to disrupt (A) Toll-like receptor signaling (Singh et al. 2012; Zhang [H] et al. 2014, 2021; Sheng et al. 2017; Chen et al. 2018; Han et al. 2018b; Castaño-Ortiz et al. 2019; Guo et al. 2019; Shane et al. 2020; Zhang et al. 2020; Zhong et al. 2020; Xie et al. 2021; Huang et al. 2022; Wan et al. 2022; Xu [L] et al. 2022; Liu et al. 2023, Tang et al. 2023) and (B) PPAR signaling (Corsini et al. 2012; Pennings et al. 2016; Sheng et al. 2017; Wu et al. 2017; Rodríguez-Jorquera et al. 2019; Shane et al. 2020; Christofides et al. 2021; Khazaee et al. 2021; Weatherly et al. 2021; Zhang [Q] et al. 2021; Camdzic et al. 2022, Chen et al. 2022; Evans et al. 2022; Wang et al. 2022; Xu [B] et al. 2022; Sun et al. 2023), but the effect of PFAS on these pathways in innate immune cells remained understudied. Black arrows and red lines with a “T” end indicate normal function (activating and inhibiting, respectively). PFAS-induced endpoints for each gene/protein are shown graphically as red up arrows (increase in signal/expression), blue down arrows (decrease in signal/expression), checkmark (binding between protein and any PFAS observed in vitro), checkmark with question mark (binding between protein and any PFAS suggested in silico, but not demonstrated in vitro). Details are provided in Supplementary Table 1. Abbreviations: CD36: Cluster of differentiation 36; E-FABP: Fatty acid binding protein [Epidermal type]; HMGB1: High mobility group box 1 protein; IκB: Nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor; IRAK: IL-1 receptor-associated kinase; MyD88: Myeloid differentiation primary response 88; NF-κB: Nuclear factor κ-light-chain-enhancer of activated B-cells; PPAR: Peroxisome proliferator-activated receptor; TLR: Toll-like Receptor; TRAF6: TNF receptor associated factor-6.