Table 1.
Toxic effects of TCDD in development of various disorders.
| Toxicity effects | Models | Doses | Duration | Toxic effects | Suggested mechanisms | References |
|---|---|---|---|---|---|---|
| Glucose metabolism disorders | Non-pregnant female C57BL/6 mice (TCDD enhanced HFD-induced obesity) | 20 ng/kg/d | 12 weeks（2x/week） | Accelerated beta cell dysfunction | ↓MafA, Slc2a2, and Nkx6.1 | Hoyeck et al. (2020) |
| Male C57BL/6 mice Female C57BL/6 mice (TCDD enhanced HFD-induced obesity) |
20 ng/kg/d | 2x/week starting one week prior to pairing with male mice and lasting throughout mating, pregnancy and lactation | Accelerated onset of hyperglycemia; Impaired glucose-induced plasma insulin levels; Reduced islet size; Increased proinsulin accumulation; Accelerated the onset of glucose intolerance without altering insulin sensitivity; Accelerated beta cell dysfunction |
↑CYP1A1, ↓AhR |
||
| C57BL/6N wild-type mice Ahr-null male mice |
5, 50, or 500 ng/kg bw | 18 days | Disturbed insulin synthesis and secretion in the pancreas; Impaired glucose uptake and glycolysis in the liver |
↓Gck | Sato et al. (2008) | |
| Mouse 3T3-L1 cells | 0.1, 1, and 10 nM | 3 days | Reduced insulin-induced glucose uptake | AhR-independent | Hsu et al. (2010) | |
| Male C57BL/6J mice Male DBA/2J mice |
100 μg/kg bw | 10 days | Increased initial blood glucose lever; Increased the activity of sucrase and lactase |
AhR ↑SGLT1 |
Ishida et al. (2005) | |
| Male C57BL/6 mice | 20 μg/kg or 200 μg/kg | A single | Males: Lost beta cell mass, increased insulin sensitivity, lost weight and induced hypoglycemia; Females: Suppressed plasma insulin levels, induced glucose intolerance but had either minimal or no changes to islet composition, insulin sensitivity and body weight |
N/A | Hoyeck et al. (2020) | |
| Male C57BL/6 mice Female C57BL/6 mice |
20 μg/kg | A single | ||||
| Fat metabolism disorders | C57BL/6N wild-type mice Ahr-null male mice |
5, 50, or 500 ng/kg bw | 18 days | Reduced cholesterol synthesis; | ↓Hmgcr and other genes | Sato et al. (2008) |
| Suppressed the lipogenesis (low-dose TCDD) | Srebf1 | |||||
| Mouse 3T3-L1 cells | 0.1, 1, and 10 nM | 3 days | Inhibited the adipogenic differentiation | ↓AhR,↓PPARγ,↓C/EBPα,↓Glut4 | Hsu et al. (2010) | |
| Male Hartley guinea pigs | 1 μg/kg | 7 days 21 days |
Inhibited the adipocyte differentiation Lost body weight accompanied by a decrease in adipose tissue weight; |
↓SREBPs | Nishiumi et al. (2008) | |
| Accumulated lipid in the liver and induced fatty liver | ↓PPARα level | |||||
| Male Ldlr−/− mice | 1 μmol/kg dioxin-like polychlorinated biphenyl 126 (PCB126) | At weeks 2 and 4 | Increased lipid droplet formation within hepatocytes | ↑CD36, IL-1β, LPL, INSIG-1 ↓Fads1, Scd1, Gyk |
Petriello et al. (2017) | |
| Male Sprague–Dawley outbred CD rats | 0, 0.4 or 40 μg/kg bw | A single | Interfered cholesterol metabolism | ↓CYP7A1, FXR, SHP, Ntcp, oatp2 | Fletcher et al. (2005) | |
| Cardiovascular diseases | C57BL/6J mice | 5 μg/kg TCDD | 3 days (continuously) | Increased in blood pressure and atherogenic lipids; Exacerbated atherosclerosis |
AhR ↑monooxygenase ↑intracellular calcium in myocytes ↓decreasing contractility |
Dalton et al. (2001) |
| Apoe+/+/hyperlipidemic Apoe−/− | 150 ng/kg, 3 times/w 10 μL dimethyl sulfoxide (DMSO) |
7 weeks | ||||
| female Harlan Sprague-Dawley rats | 0, 3, 10, 22, 46, 100 ng/kg/d | 14, 31, 53 weeks | Increased risk of cardiomyopathy and chronic active arteritis (in mesentery and pancreas); Increased vascular permeability |
Cytosolic AhR activation ↑oxidative stress ↑ROS release |
Jokinen et al. (2003) | |
| female Sprague-Dawley rats (1/2 ovariectomy) | PCB126: First 2 times 64 μg/kg Follow: 32 μg/kg |
12 weeks | Increased myocardial weight; Reduced serum triglyceride levels; Increased HDL cholesterol levels |
N/A | Lind et al. (2004) | |
| EP3 knockout (EP3−/−) mice wild-type (WT) C57BL/6 | 10 μg TCDD/kg | 10 days | Induced endothelial injury (atherosclerosis); Triggered HUVECs apoptosis |
↑COX-2, PG, p38 ↓Bcl-2 |
Yu et al. (2017) | |
| Undifferentiated HepaRG cells | N/A | 48 + 24h | Triggered cell apoptosis; Upregulated TRAIL |
↑BMF, expression of constituents and/or transcriptional targets of signaling pathways | Svobodová et al. (2019) | |
| Liver injury | Male C57BL/6J mice | 10% low-fat (LFD)/45% high-fat (HFD) 5 μg/kg TCDD |
14 weeks | Triggered hepatic steatosis and hepatic fibrosis; | ↑Cd36, PPARg ↓MTTP, DGAT1, PKLR, Slc2a2/Glut2 |
Duval et al. (2017) |
| Male ApoE−/− mice | 15 μg/kg | 6 weeks/4 times | Triggered liver steatosis, liver necrosis and inflammatory stimuli | Activated Nrf2 ↑ALT, AST, CYP1A1 |
Shan et al. (2015) | |
| Male Sprague-Dawley rats | 8 μg/kg 15 mg/kg |
21 days | Inhibited hepatic antioxidant activity; Increased formation of MNHEPs |
Inactivated antioxidant enzymes ↑ROS, LPO |
Türkez et al. (2012) | |
| Male C57BL/6J | 0.3, 3, or 30 μg/kg TCDD | 4 days | Increased neutrophil chemokines (plasma concentration) | ↑ALT, IFNγ ↓KC |
Fullerton et al. (2013) | |
| Pregnant female C57BL/6J mice | 3 μg/kg | 14 days | Increased liver weight; Induced lipid peroxidation |
↑SOD, GSH-Px, CAT, GSH ↓MDA |
Ciftci et al. (2013) | |
| Neurodegenerative diseases | Pregnant Sprague-Dawley rats | 10−11 to 10−10 mol/L | 18 days | Increased NFL's mRNA and protein | ↑phosphorylation of NFL, ERK1/2, p38 | Chen et al., 2020a, Chen et al., 2020b |
| CGC from AhR−/− cell from AhR-null mice | 1–500 nM | N/A | Triggered cell loss; Induced DNA laddering |
AhR ↑CYP1A2, caspase-3 |
Sánchez-Martín et al. (2011) | |
| Female Sprague-Dawley mice | 0.5 LD50 25 μg/kg | 7 days | Triggered apoptosis of neuronal cell lines | Wnt/β-catenin pathway ↓pSer9-GSK-3β ↓β-catenin |
Xu et al. (2013) |
↑- increase; ↓- decrease; N/A, not available.
Acronyms: AhR, aryl hydrocarbon receptor; ALT, alanine transaminase; AST, aspartate aminotransferase; Bcl-2, B-cell lymphoma 2; BMF, Bcl-2 modifying factor; C/EBPα, CCAAT/enhancer-binding protein α; CAT, catalase; CD36, cluster of differentiation 36; CGC, cerebellar granule cell; COX-2, cyclooxygenase-2; CYP1A1,cytochrome P450 1A1; CYP1A2, cytochrome P450 1A2; CYP7A1, cytochrome P450 7A1; DGAT1, diacylglycerol acyltransferases; ERK1/2, extracellular signal-regulated kinase; Fads1, fatty acid desaturase 1; FXR, farnesoid X receptor; Gck, Glucokinase; Glut4, glucose transporter type 4; GSH, glutathione; GSH-Px, glutathione peroxidase; Gyk, glycerokinase; Hmgcr, 3-hydroxy-3-methylglutaryl-CoA reductase; HUVEC, human umbilical vein endothelial cells; IFNγ, interferon γ; INSIG-1, insulin induced gene 1; KC, keratinocyte chemoattractant; LPL, lipoprotein lipase; LPO, lactoperoxidase; MDA, malondialdehyde; MNHEP, hepatocyte micronuclei; MTTP, microsomal triglyceride transfer protein; NFL, neurofilament light; Nrf2, nuclear factor erythroid 2-related factor 2; Ntcp, sodium taurocholate co-transporting polypeptide; oatp2, Slc21a5; p38, mitogen-activated protein kinase; PG, prostaglandin; PKLR, kyruvate kinase L/R; PPARg, peroxisome proliferator-activated receptor g; PPARα, peroxisome proliferator-activated receptor α; PPARγ, peroxisome proliferator-activated receptor γ; pSer9-GSK-3β, phospho-glycogen synthase kinase-3β; ROS, reactive oxygen species; Scd1, stearoyl-CoA desaturase 1; SGLT1, sodium–glucose co-transporter 1; SHP, short heterodimer partner; Slc2a2/Glut2, solute carrier family 2 member 2/glucose transporter 2; SOD, superoxide dismutase; Srebf1, sterol regulatory element binding factor 1; SREBP, sterol regulatory element binding protein; TRAIL: tumor necrosis factor (TNF)-related apoptosis-inducing ligand; Wnt, wingless-related integration site.