Table 9.
OTA carcinogenicity and genotoxicity.
| Year | Nephrotoxicity testing | References |
|---|---|---|
| 1978 | OTA induces renal and hepatic tumors in mice. | [177] |
| 1984 | OTA is carcinogenic for mice. | [178] |
| 1984 | CIT increases OTA carcinogenicity. | [179] |
| 1987 | OTA carcinogenicity to humans: OTA classified in Group 3 (not classifiable as to its carcinogenicity to humans). | [180] |
| 1989 | Male rats are more susceptible to renal tumors than female rats (NTP study). | [181] |
| 1989 | The genotoxicity of ochratoxin A is reviewed. | [35,182] |
| 1991 | OTA-DNA adducts: For the first time, OTA-DNA adducts are found in the kidney, liver, and spleen of mice. | [183] |
| 1993 | OTA is re-classified as a possibly carcinogenic to humans based on a great amount of evidence of carcinogenity in several animal studies of 2B in 1993. | [11] |
| 1993 | OTA-DNA adducts: Other studies take place in mice and rat tissues after acute and subchronic exposure, and in urinary tract tumors (UTT) of Bulgarian subjects. | [184,185,186] |
| 1993-2009 | OTA-DNA adducts are also detected in tissues of humans presumably exposed to OTA in several countries (Bulgaria, Serbia, Croatia, Germany, Belgium, France, Tunisia). | [16,17,185,187,188,189,190] |
| 1998-2002 | DNA adduction following chronic exposure (carcinogenic study) of rats to OTA first described; sex differences and dual mechanism—oxidative pathways and DNA adduction—are observed | [12,13,191] |
| 1998 | OTA-DNA adducts are observed in mother and progeny of mice fed OTA nine months after birth male mice develop cancer. | [192] |
| 2000–2001 | In vitro formation of dG-OTA adduct. | [193,194] |
| 2001–2002 | Other studies with radiolabeled OTA were unable to detect any DNA binding of OTA, but explanation of this discrepancy is given in depth by Pfohl-Leszkowicz and Castegnaro in 2005 [ 195] | [60,196] |
| 2003 | OTA-DNA adduct in pigs subchronically exposed to low doses of OTA. Relation with biotransformation. | [197] |
| 2002–2010 | OTA may be involved in testicular cancer. | [175,198,199,200,201] |
| 2003–2008 | CIT increases genotoxicity of OTA and modifies the metabolism of rats exposed to low doses for three weeks. | [202,203] |
| 2004 | Evidence for covalent DNA adduction by OTA following chronic exposure to OTA in rats (and subacute exposure in pigs). | [190] |
| 2004 | Another research group, using the highly sensitive accelerator of the mass spectrometry technique, does not detect DNA adducts after the administration of 14C-labeled OTA to rats. | [204] |
| 2004 | In 2004, a review of the NTP experimental rat tumor data for OTA also places OTA in the category of “chemicals inducing renal tumors through direct interaction of the parent compound or metabolite with renal DNA” based on histopathological evidence. | [205] |
| 2004–2010 | The long-term OTA studies confirm the incidence of tumors in rats; in male rats, these tumors are related to OTA dose | [205,206,207] |
| 2004–2012 | OTA is a direct genotoxic forming covalent DNA adducts in the kidney OTA can indeed react with DNA via a phenolic radical resulting in C8-deoxyguanosine adduct (synthetized and chemical identified by mass spectrum). | [175,190,201,207,208,209] |
| 2006 | Confirmation of OTA genotoxicity via measurement of comet in rat kidneys. | [210] |
| 2007 | Chronic exposure to low OTA doses can be much more damaging than acute exposure to a high dose. | [16] |
| 2007 | DNA diploidy in rat tumors is associated to genetic damage. | [211] |
| 2007 | OTA induces an increase of mutation at two loci—hypoxantine-guanine phophoribosyl transferase (HPRT) and thymidine kinase (TK). | [212] |
| 2008 | DNA adduct cannot be confirmed, but the explanation is given by Pfohl-Leszkowicz et al. (2009) [64] | [213] |
| 2008 | Correlation between biotransformation of OTA and direct covalent binding on DNA. | [214] |
| 2009 | It is found that the kidney DNA adduct pattern of BEN patients is similar to the kidney DNA adduct pattern of pigs living in the same farm and pigs co-exposed to OTA, fumonisins, and citrinin. | [17] |
| 2009 | A different proposal of mechanism for OTA-mediated renal carcinogenesis and threshold model for its risk assessment. | [215] |
| 2009–2010 | Identification by LC-MS/MS of these DNA adduct in rat tissues. | [64,201] |
| 2010 | OTA is carcinogenic for poultry. | [216] |
| 2011 | Induction of mutation only in medulla of rat kidney exposed to carcinogenic dose. | [217] |
| 2012 | Relation structure activity studies clearly indicate that OTHQ (ochratoxin hydroxyquinone) is responsible of direct genotoxicity, whereas some others are cytotoxic. | [65,209] |
| 2012 | OTA is activated to a species that is a directly genotoxic mutagen. OTHQ in presence of cysteine is also mutagenic. | [218] |
| A new approach to cancer represents miRNA. | [219,220] | |
| 2013 | The induction of miR-132 and miR-200c by OTA elevates reactive oxygen species (ROS) levels and profibrotic (profibrotic transforming growth factors β, TGFβ) expression. | [221] |
| 2014 | OTA has the potential to initiate or support the development of fibrotic kidney diseases by involving post-transcriptional regulation mechanisms comprising miR-29b. OTA reduces the impact of miR-29b and thus enhances collagen protein expression. | [222] |
| 2014 | A low dose of OTA induces micronuclei, and OTA delays the DNA repair kinetics. | [223] |
| 2014 | OTA increases proliferating cell nuclear antigen after 13 weeks in kidney and kidney damages. Limited oxidative stress. | [224] |
| 2015 | Dietary exposure to OTA represents a serious health issue, including urinary tract tumors in humans. | [50] |