Table 6 Modulation of calcium homeostasis by PFAS in immune-relevant cells (see also Experimental studies on modulation of calcium signalling by PFAS in immune cells section, Results)

PFOS

In vitro: murine bone marrow-derived macrophages (BMDMs) and human cells (THP-1-derived macrophages)

In vivo, wild type (WT) C57BL/6 J mice, i.p. injection (5, 15, or 25 mg/kg/d for 5 days; 0.066 mg/kg/d for 30 days)

cytosolic Ca²⁺was increased in human and mouse macrophages (starting at 150 μM, appr. ~↑ 40% relative to control in BMDMS; in Thp-1 cells ~↑20% at 50 μmM, ~↑40% at 100 and 150 μM), concurringly with the protein level of BiP, an indicator of ER stress. The authors concluded that PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca²⁺-PKC-NF-κB/JNK-BAX/BAK axis

[158]

PFOS, PFOA, F-53B, PFHxS

In vitro:gene expression profiles in hBMSC at 100 nM after 7 d; perturbation of Ca2+ signalling at 1 – 100 μM by real-time imaging

Genes related to osteoblast differentiation, ERK1/2, TGFß and Ca2+ signalling were affected.

Ca2+ transients occurred at 10 μM and 100 μM for F-53B, and at 100 μM for PFOS and PFHxS, but not PFOA.

[163]

PFOS

In vitro: IgE stimulated RBL-2H3 cells treated +/− PFOS for i.c. Ca²⁺-measurement (also histamine and β-hexosaminidase)

In vivo: ovalbumin-induced active systemic anaphylaxis model using ICR mice to assess for type I hypersensitivity. After sensitization, mice were treated p.o. with PFOS (50-150 mg/kg 3 times on day 9, 11 and 13, day 14 ovalbumin i.p. → measurement of allergic symptoms (serum histamine, IgE, IgG₁, TNF-α and rectal temperature)

increase in i.c. Ca²⁺-levels (at 500 μM with challenge at 50, 100, 500 μM), likely caused by crosslinking of FcεRI on mast cells; consequences:

- the release of histamine and β-hexosaminidase and degranulation through membrane fusion was increased in IgE-stimulated mast cells;

- Induction of transcription factor NF-κB;

- regulation of expression of pro-inflammatory cytokines and chemokines at high concentrations (100, 500 μM);

[160]

PFDA (C10), PFUnA (C11), PFNA (C7), PFHpA (C9)

In vitro: IgE stimulated RBL-2H3 cells treated +/− different PFAS (100 μM) for i.c. Ca2 + −measurement (also histamine and β-hexosaminidase);

Cells +/− NF-κB luciferase transporter construct

In vitro: long-chain PFDA and PFUnA increased release of histamine and β-hexosaminidase by up-regulation of i.c. Ca²⁺ levels, whereas PFNA and PFHpA did not

[111]

PFOA

In vitro: RBL-2H3 – mast cell like cells, expressing FcεRI, stimulated with IgE (100-500 μM PFOA)

In vitro: Increase in i.c. Ca²⁺ levels (100 – 500 μM), which caused augmented mast cell degranulation (increased release of histamine and β-hexosaminidase)

[159]

PFOA

In vitro: mast-cell mediated allergic inflammation HMC-1 cells treated with 25–150 μM for 24 hrs, 200 μM for 10 min (for intracellular Ca²⁺⁾

In vitro: increase of i.c. Ca²⁺ causing

- histamine release

- expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8)

- NF-κB, p38 mitogen-activated protein kinase (but not JNK and ERK), and caspase-1 dependent.

[128]