Table 1.
Summary of Key Findings Associated with Arsenic-Induced Compromised Protein Quality Control
| components of the proteostasis network | experimental system | Reagent used | concentration; exposure time | refs |
|---|---|---|---|---|
| Mitochondrial Homeostasis | ||||
| mitochondrial DNA damage | AL human-hamster hybrid cells, CHOK1 cells stably expressing a single copy of human chromosome 11 | NaAsO2 | 0.5–1 μg/mL; 60 d | 26 |
| uncoupling of mitochondrial respiration through metabolic reprogramming | C. elegans | NaAsO2 | 50, 250, or 500 μM; 12–48 h | 27 |
| Cultured human cells (BEAS-2B, RWPE-1, A549, HUC and HDF) | NaAsO2 | 0, 1, or 5 μM; 1–2 wk | 30 | |
| BEAS-2B, cancer stem-like cells | NaAsO2 | 0.25 μM; 3–7 d | 31 | |
| excessive production of ROS | AL hybrid cells | NaAsO2 | 2 μg/mL; 5 min | 25 |
| 3xTgAD mouse model | NaAsO2 | 3 ppm (0.2 mg/kg/day); 6 mo | 28 | |
| elevated proton leak by ROS-induced depolarization and lipid peroxidation | C. elegans | NaAsO2 | 0, 50, or 500 μM; 48 h | 27 |
| Molecular Chaperones | ||||
| interference with substrate binding to chaperone proteins | S. cerevisiae | NaAsO2 | 1 mM; 1 h | 42 |
| disruption of activities of ATP-dependent chaperones | HeLa cells | NaAsO2 | 50, 100, 200, 400, 500 μM; 1–4 h | 43 |
| induction of protein aggregation of molecular chaperones | S. cerevisiae | NaAsO2 | 50, 100, 200, 400, 600 μM; 120 min | 41 |
| 1-day-old male chickens/cocks | As2O3 | 7.5, 15, and 30 mg/kg | 45 | |
| In vitro (e.g., murine NIH-3T3 cells) and in vivo (e.g., rodent) | NaAsO2 | 1–300 uM; 1–16 h (in vitro); 0.8–6 mg/kg; 1–24 h (in vivo) | 44 | |
| GM00637 human fibroblast cells | NaAsO2 | 5 μM; 24 h | 46 | |
| C. elegans | NaAsO2 | 100 mM; 4 d | 47 | |
| Pro-inflammatory Pathways and ER Stress | ||||
| activation of inflammatory response | porcine cells from fresh aortas | NaAsO2 | 0.5, 2, 5 μM; 0.5–2 h | 53 |
| circulating lymphocytes from arsenic-exposed human subjects | Blood arsenic | 0–4.32, 4.64–9.00, 9.60–46.50 μg/L | 54 | |
| human infants born to arsenic-exposed mothers | Arsenic | maternal toenail ≥0.5 μg/g | 55 | |
| female C57BL/6 mice (6–7 weeks old) | NaAsO2 | 0, 2.5, 5, 10 mg/kg; 24 h | 56 | |
| male Sprague-Dawley rats | NaAsO2 | 0, 5, 10, 20, 50, 100 ppb; 7, 14, or 28 d | 57 | |
| reduction of phagocytic receptors on immune cells | exposed rural women from districts of 24 Parganas (south) | arsenic | 11–50 μg/L; lifetime (22–45 yr) | 58 |
| induction of ER stress | RIN-m5F rat insulinoma pancreatic β-cell line | As2O3 | 0, 2, 5 μM; 8, 16, 24 h | 61 |
| SKH-1 hairless mice | NaAsO2 | 50, 100, 200 ppm; 1 mo | 62 | |
| RAW 264.7 mouse macrophage cells | As2O3 | 0, 0.2, 2 μM; 1 or 3 h | 63 | |
| Neuro-2a murine neuroblastoma cells | As2O3 | 5 μM; 6, 12, or 24 h | 64 | |
| SVEC4–10 mouse vascular endothelium cells | As2O3 | 5 or 7.4 μM; 16 h | 65 | |
| enhanced APP processing and Aβ oligomerization | cholinergic SN56.B5.G4 cells, primary neuronal cells derived from transgenic Tg2576 mice overexpressing human APPswe | NaAsO2 or DMA | 5 or 10 μM; 12 or 24 h | 66 |
| male Wistar rats | NaAsO2 | 3.80 ppm; 68 d | 67 | |
| Ubiquitin-Proteasome System | ||||
| impairment of enzymatic activities of ZnF-containing E3 ubiquitin ligases | GM00637, HeLa cells | NaAsO2 | 1, 2, 4, 5 μM; 24 h | 73 |
| HEK293T cells | NaAsO2 | 1, 3, 5 μM; 24 h | 74 | |
| GM00637, IMR90, and HEK293T cells | NaAsO2 | 5 or 20 μM; 8 or 24 h | 75 | |
| NB4 APL cells | As2O3 | 1–2 μM; 1–24 h | 77 | |
| compromising functions of p97 and proteasome | NIH3T3, DTC25 cells | arsenate | 50 or 250 μM; 0–25 min or 16 h | 72 |
| Autophagy | ||||
| impairment of TORC1-mediated protein sequestration to autophagosome | BEAS-2B cells | NaAsO2 | 0.25 μM; 24 h, 1 wk or 16 wk | 85 |
| S. cerevisiae | NaAsO2 | 50, 100, 200, 500 μM; 5, 10, or 30 min | 88 | |
| inhibition of autophagic flux via sustained Nrf2 activation | HEK293T cells | NaAsO2 | 1, 3, 5 μM; 24 h | 74 |
| BEAS-2B, HBE cells | NaAsO2 | 125, 250, 500 nM, 1, 4, or 10 uM; 4 or 16 h | 84 | |
| HaCaT human keratinocytes | NaAsO2 | 8 uM; 6 h | 89 | |
| suppression of autophagosome-lysosome Fusion | NIH3T3 cells | NaAsO2 | 0.25, 0.5, 1, or 2 μM; 2 or 4 h | 86 |
| HeLa, HEK293T, NIH3T3, iBMKs cells | NaAsO2 | 0, 0.5, 1, 2 μM; 4 h | 87 | |
| sustained overproduction of IL-6 | BEAS-2B cells | NaAsO2 | 0.25 μM; 24 h, 1 wk or 16 wk | 85 |
| Asymmetric Segregation and Axonal Transport of Damaged Proteins | ||||
| disturbed mitotic progression and aberrant positioning of mitotic spindles | G2-enriched HFW cells | NaAsO2 | 5 μM; 18 h | 99 |
| HeLa-S3, CGL2 cells | NaAsO2 | 1 or 3 μM; 20 h | 100 | |
| attenuated microtubule dynamics and abnormal mitotic morphologies | HeLa-S3 cells | NaAsO2 | 5, 10, 20, 50 μM; 1, 2, or 24 h | 102 |
| Asymmetric Segregation and Axonal Transport of Damaged Proteins | ||||
| inhibition of TRiC for folding and oligomerization of cytoskeleton components | S. cerevisiae | NaAsO2 | 1 mM; 3 h | 42 |
| decreased light subunit of neurofilament | male Wistar rats | NaAsO2 | 15 or 20 mg/kg; 3, 6, or 9 h | 106 |
| augmented phosphorylation of tau | Chinese hamster ovary (CHO) T40 cells | NaAsO2 | 500 μM; 2 h | 107 |