Evidence for a Role of Oxidative Stress in the Carcinogenicity of Ochratoxin A

Table 1

OTA oxidative stress-related studies.

Model	Gender	Via	Time treatment	Dose	Aim	Results/Conclusion	Ref.
BALB/c macrophage J774a cell line			24, 48, 72 h	30 nM–100 μM	OTA immunotoxicity and modulation inflammatory process	Induction of iNOs, COX-2 and NF-κb expression by OTA. OTA is an immunotoxic compound	[51]
Porcine kidney tubuli cells LL-PK1			6–24 h	1–100 μmol/L	Characterization effect of OTA on Nrf2 response	Nrf2 potential signal transduction pathway by which OTA impairs its own detoxification	[45]
Porcine kidney tubuli cells LL-PK1			24 h	1–100 μmol/L	Impact of OTA on Nrf2, AP-1 activity, antioxidant enzymes and GST	Enhanced production of ROS, GST impairment. Nrf2 and AP-1 disruption by OTA. Impairment of the detoxification machinery	[44]
Rat Sprague-Dawley	male	diet	15 days	3.0 mg/kg bw	Oxidative stress protection study	OTA-induced oxidative stress chemoprotection by Inula crithmoides	[102]
Rat F344	male	gavage	7 and 21 days	0.5 mg/kg bw	Mechanism of action study-microarrays	Oxidative stress, calcium homeostasis, cytoskeleton structure	[61]
Human hepatocytes HepG2; Monkey kidney Vero cells				0–100 μM	Decrease GSH	No induction of heat shock protein (HSP)	[103]
Rat Wistar	male	diet	15 days	5 ng/g bw 50 ng/kg bw	Oxidative damage study (proteins and lipids)	Malondialdehyde (MDA) and protein carbonylation (PC) increase in kidney > liver	[76]
Chinese Hamster lung V79 cells; Lymphoma mouse LY5178 cells				0–438 μM	OTA mutagenicity	OTA is mutagenic at cytotoxic doses in mammalian cells via oxidative DNA damage induction.	[104]
Rats Sprague-Dawley	male	diet	4 weeks	200 ppb	Oxidative stress protection study	OTA-induced oxidative stress and DNA damage chemoprotection by cyanidin 3-O-β-D-glucoside	[105]
Pig kidney cell line LLC-PK1			24 h	0, 10, 15, 20 μM	Oxidative stress protection study	OTA-induced ROS. Scavenging by cathechins (epigallocathechin gallate (EGCG) and epicatechin gallate (ECG))	[106]
Human epithelial colorectal adenocarcinoma Caco-2 cells				100 μM	Effect of OTA on barrier function impairment	Loss of microdomains associated with tight junctions maybe due to oxidative events	[107]
Neural stem/progenitor cells (NSCs)				0.01–100 μg/mL	Vulnerability of brains mouse cells to OTA	Robust increased in total and mitochondrial SOD activity. OTA impaired hippocampus neurogenesis	[108]
Rats	Male/liver and kidney	Diet (drinking water)	4 weeks	289 μg/kg	Oxidative stress protection study	Melatonin protection against OTA-induced oxidative damage in liver and kidney. CoQ protective in liver.	[79]
Human renal cell line HK-2			6 and 24 h	50 μM	Mechanism of action study-microarrays	Significant increase in ROS level and oxidative DNA damage.	[61]
Human renal proximal tubular epithelial cell line HK-2				50–800 μM	Evaluate single-strand DNA breaks and oxidative damage induction by OTA	Oxidative stress precedes cytotoxicity and genotoxicity	[57]
Male Fischer 344; Primary hepatocytes; adherent proximal tubules epithelial NRK cells; rat liver RL-34			Rats 2 years; in vitro culture 24–48 h;	300 μg–100/kg bw; 1.5–6.0 μM	Demonstration of cellular defense reduction by OTA	OTA induces depletion of antioxidant defense by inhibition of Nrf2 responsible of oxidative stress response	[46]
Eker and wild type rats	male	gavage	1–14 days	210 μg/kg bw	Early carcinogen-specific gene expression study	Oxidative DNA damage response genes, general stress response, and cell proliferation	[109]
Wistar rats		gavage	90 days	289 μg/kg bw	Early effects of chronic OTA administration in liver	Reduction in the ability to counteract oxidative stress in liver	[63]
Swiss ICR	male	i. p	6, 24, 72 hours	0–6 mg/kg bw	Oxidative stress and OTA neurotoxicity	Acute depletion of striate DA on a background of globally increased oxidative stress and transient inhibition of oxidative DNA repair	[110]
Swiss mice	male	I.p; infusion	2 weeks	Acute 3.5 mg/kg; chronic 4, 8, 16 mg/kg	Effect of chronic low dose OTA exposure on regional brain oxidative stress and stratial DA metabolism	Low doses exposure caused global oxidative stress	[111]
F344 rats	male	diet	7 and 21 d; 4, 7 and 12 months	300 mg/kg bw	OTA mechanism of action-microarrays study in liver and kidney	Oxidative stress and metabolic response modulated involving mainly Nrf2 and HNF4α pathway disruption	[47]
Swiss mice	male	oral	24 hours	10 mg/kg	Immune cells response after acute OTA exposure	OTA-induced oxidative stress response responsible of its own toxicity.	[112]
Wistar rats	female	Intraperitoneally	7, 14 and 21 days	0.5 mg/kg bw/day	Genotoxic potential of OTA measuring DNA strand breaks (comet assay) in the kidney	OTA-induced DNA strand breaks were detected, OTA concentration in the kidney and duration of the treatment correlated with severity of the DNA damage	[62]
Wistar rats	male	Oral	15 days	5 ng; 0.05 mg; 0.5 mg/bw	Effect of OTA on DNA damage	Oxidative stress responsible for OTA-DNA damage as shown by Fpg-modified comet assay	[113]
Pig kidney microsomes, human bronchial epithelial cells, human kidney cells			Cells: 2, 7, 24 hours	0.5, 1.0, 2.5 μM	Genotoxicity of the hydroquinone (OTHQ) metabolite of OTA	OTQ-mediated adduct spots form in a dose-and-time-dependent manner	[114]
Wistar rats	female	oral	7, 14 and 21 days	0.5 mg/kg bw	Effect of OTA on protein oxidation in kidney and liver	Increased protein carbonyls in the kidney and liver	[68]
F344 rats	male	gavage		0.03, 0.10, 0.30 mg/kg bw	Evaluate relevance of OTA-induced oxidative damage on nephrotoxicity and carcinogenicity	Tumours in rat kidney may be attributable to oxidative DNA damage in combination with cell-specific cytotoxic and proliferation-stimulating effects as cell-signaling response	[69]
V79 (Chinese hamster lung fibroblasts) cells, CV-1 (African green monkey, kidney) cells, primary rat kidney cells			1–24 hours	2.5, 100 μmol/L OTA	Relevance of OTA-induced oxidative damage in nephrotoxicity and carcinogenicity	Cytotoxicity and oxidative DNA damage already at low doses could be a relevant factor for the nephrocarcinogenicity	[58]
Rat lymphoid cells			1 hour	0.5, 2, 20 μM	OTA immune function modification	Protein synthesis inhibition, oxidative metabolism of OTA, prostaglandin synthesis implicated in NK cells toxicity	[115]
Human hepatoma—derived cell lines (HepG2), human colonic adenocarcinoma cell line (Caco-2)			24, 48, 72 hours	0–100 μM	Oxidative stress protection study	OTA-induced oxidative stress damage. Protective effect by Cyanidin-3-O-β glucopyranoside (C-3-G)	[116]
F344 Fischer rats	male	gavage	2 weeks	0–2000 μg/kg bw	Genotoxicity of OTA	DNA strand breaks in target and nontarget tissues probably involving oxidative stress mechanism	[60]
Human hepatoma—derived cell line (HepG2)			48–72 hours	35–10 mM	Oxidative damage protection study	No cytotoxicity protection observed with Vitamine E, polyphenols	[117]
Sprague-Dawley	male	diet	15 days	3 mg/kg	Oxidative stress protection in vivo study	Preventive effect against OTA-induced oxidative stress and lipid peroxidation by melatonin	[75]
Human fibroblast cells			48–72 hours	0–50 μM	Oxidative stress protection study	Reduction of free radical species production and DNA damage prevention by cyanin 3-O-β-D-glucoside (C3G)	[118]
Fetal rat telencephalon aggregating cells			24–48 hours, 9 days	0–20 nM	Adverse effect of OTA in brain	Brain inflammatory response induction of HO-1, iNOs, PPARγ, cytoskeletal damage	[50]
Human hepatoma-derived cell line (HepG2)			24 hours	0–40 μg/mL	Genotoxicity of OTA	Dose-dependent induction of DNA single strand breaks (comet assay) and micronuclei (MN)	[119]
Primary proximal tubules renal (PT) cells, proximal tubular cell line (LLC-PK1)			0–24 hours	0–100 μM	OTA mediated oxidative stress response in proximal tubular cells, oxidative stress protection	Oxidative stress contributes to tubular toxicity. Antioxidants (α-tocopherol, N-acetyl-Lcysteine (NAC) treatment prevents OTA toxicity	[59]
Wistar rats	male	gavage	10, 30, 60 days	120 μg/kg bw	Kidney low dose OTA response: sequence of events leading to cell death	Low dose induces oxidative stress, apoptosis in proximal, and distal tubule kidney cells	[78]
Human hepatoma—derived cell line (HepG2)			1 hour, 24 hours	0–50 μg/mL	Genotoxicity of OTA	No inductions of mutations in the Ames assay, a dose-dependent induction of micronuclei in the MN assay, and DNA migration (comet assay) were detected	[120]
Proximal tubular cells (PTC), Wistar rats	male	gavage	24–72 hours (in vivo and in vitro)	5.0 μM, 12.5 μM in vitro; 1 and 10 mg/kg bw	In vivo and in vitro gene expression comparative study	In vitro and in vivo gene expression data were comparable. Response to oxidative stress-related genes hypoxia-inducible factor 1 and catalase was observed	[121]
Dark Agouti (DA), Lewis rats	male	Intragastric intubation	0.4 mg/kg bw	Life-time	Life-time study to evaluate if MESNA leads to a more effective reduction of OTA-induced tumour development or urinary tract damage	Lack of effect of mesna on OTA-induced urinary tract damage or renal tumor development	[122]
Dark Agouti (DA), Lewis rats	male	Intragastric intubation	0.4 mg/kg bw	2 years	Life-time study to evaluate the potential protective effect of 2 mercaptoethane sulfonate (MESNA) and N-acetyl cysteine (NAC )	MESNA decreased karyomegalies in kidney, but had no beneficial effect on renal tumour incidence	[123]
Fischer rats	male	gavage	4, 8, 24, 48 hours	0–2.0 mg/kg bw	Chemical and biological markers induced by OTA exposure associated with oxidative stress	Oxidative stress may contribute to mechanism of OTA renal toxicity and carcinogenicity in rats over long term exposure	[77]
Bronchial epithelial cells incubated with microsomes of seminal vesicles of pig			4 hours	10 μM	Roles of cyclooxygenase and lipoxygenase in ochratoxin A genotoxicity in human epithelial lung cells	OTA is biotransformed into genotoxic metabolite via a lipoxygenase, whereas prostaglandin—H-synthetase (PGHS) decreases OTA genotoxicity	[124]
Sprague-Dawley liver microsomes, liver mitochondria and hepatocytes cells	female			2.5 mM	Free radical generation by OTA in hepatocytes, mitochondria, and microsomes using electron paramagnetic resonance (EPR)	Oxidative damage may be one of the manifestations of cellular damage in the toxicity of OTA	[125]
Bacillus brevis			10 min	1 mg/mL	Study free radical generation in bacteria as model system	OTA induces free radical production, enhancing permeability of the cellular membrane to Ca2^+	[37]
Swiss mice	Male	Gastric intubation	48 hours	2 mg/kg bw	Effects of vitamins on genotoxicity of OTA	Vitamins E, A, and C also reduced OTA-DNA adduct formation in mice kidney	[126]
Wistar rat	male	Gastric intubation	Every 48 hours/3 weeks	289 μg/kg body weight	Protective effect of superoxide dismutase (SOD) and catalase	SOD + catalase prevents the nephrotoxicity induced by OTA in rats	[127]
Wistar rat liver microsomes, kidney microsomes	male			6 mg/kg bw	Lipid peroxidation induction by OTA	lipid peroxidation may play a role in the observed toxicity of ochratoxin A	[73]