Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression

Hibi, Daisuke; Kijima, Aki; Kuroda, Ken; Suzuki, Yuta; Ishii, Yuji; Jin, Meilan; Nakajima, Masahiro; Sugita-Konishi, Yoshiko; Yanai, Tokuma; Nohmi, Takehiko; Nishikawa, Akiyoshi; Umemura, Takashi

doi:10.2131/jts.38.57

Cited by 40 publications

(30 citation statements)

References 45 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the present study, on the other hand, OTA treatment increased the mRNA levels of Nfe2l2, Gpx1, Gpx2, Gstm1 and Mapk8, but it reduced the mRNA levels of Gsta5, Prdx1 and Txn1. Hibi et al (2013) have shown similar fluctuations in the mRNA levels of oxidative stress-related genes in the OSOM by OTAtreatment in rats (Hibi et al, 2013). While pattern of responses are Fig.…”

Section: Discussionmentioning

confidence: 62%

“…OTA has shown to fluctuate transcript levels of various genes encoding anti-oxidative enzymes as well as those related to DNA double-strand breaks and cell cycle progression in the rat kidney in gene expression microarray analysis (Marin-Kuan et al, 2006;Hibi et al, 2013). It has been suggested that antioxidants may protect proximal tubular damage and prevent the induction of karyomegaly by OTA in rats; however, antioxidant treatment was not effective for preventing induction of renal carcinogenicity (Di Giacomo et al, 2007;Pfohl-Leszkowicz et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats

Taniai

Yafune

Nakajima³

et al. 2014

Toxicology Letters

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats

Taniai

Yafune

Nakajima³

et al. 2014

Toxicology Letters

Self Cite

View full text Add to dashboard Cite

“…Although the mechanism that leads to OTA genotoxicity, as measured through the comet assay, is not fully understood, evidence from in vitro (with different cell types) and in vivo studies suggests the role of oxidative stress (Ali et al, 2014;Arbillaga et al, 2007;Aydin et al, 2014;Hadjeba-Medjdoub et al, 2012;Hibi et al, 2013aHibi et al, , 2013bLebrun and Föllmann, 2002;Yang et al, 2014). It has also been reported that OTA biotransformation produces metabolites that are more genotoxic than the original toxin.…”

Section: Discussionmentioning

confidence: 99%

“…The first hypothesis suggests that the carcinogenicity of OTA is linked to its epigenetic nature because OTA produces effects in target cells that either indirectly lead to neoplasic transformation or facilitate the development of neoplasms from cytogenetically transformed cells (O'Brien and Dietrich, 2005;Schilter et al, 2005;Turesky, 2005). The second hypothesis suggests that its carcinogenicity is due to genotoxic mechanisms (Hibi et al, 2013a(Hibi et al, , 2013bManderville, 2005;Mantle et al, 2010;Pfohl-Leszkowicz and Castegnaro, 2005). In any case, OTA has been classified as a possible group 2B human carcinogen by the International Agency for Research on Cancer (IARC, 1993).…”

Section: Introductionmentioning

confidence: 99%

Low doses of ochratoxin A induce micronucleus formation and delay DNA repair in human lymphocytes

González-Arias

Benítez-Trinidad

Sordo

et al. 2014

Food and Chemical Toxicology

View full text Add to dashboard Cite

The contamination of food commodities by fungal toxins has attracted great interest because many of these mycotoxins are responsible for different diseases, including cancer and other chronic illnesses. Ochratoxin A (OTA) is a mycotoxin naturally present in food, and long-term exposure to food contaminated with low levels of OTA has been associated with renal cancer. In the present study, the cytotoxicity, cytostaticity, and genotoxicity of OTA (0.075-15 µM) in human lymphocytes were evaluated. A comet assay, a modified comet assay (DNA repair assay), which uses N-hydroxyurea (NHU) to detect non-repaired lesions produced by OTA, and a cytokinesis-blocked micronucleus assay were used. Treatments with OTA were not cytotoxic, but OTA caused a cytostatic effect in human lymphocytes at a concentration of 15 µM. OTA (0.075-5 µM) produced a slight increase in the percentage of DNA in the comets and a delay in the DNA repair capacity of the lymphocytes. Micronucleus (MN) induction was observed at OTA concentrations of 1.5 and 5 µM. Our results indicate that OTA induces DNA stable damage at low doses that are neither cytotoxic nor cytostatic, and OTA delays the DNA repair kinetics. These findings indicate that OTA affects two pivotal events in the carcinogenesis pathway.

show abstract

“…44,47,48 1993 IARC raporunda, OTA ile ilgili genotoksisite verilerinde negatif sonuçlara yer verilse de mevcut birçok çalışmada, OTA'nın insan hücrele-rinde, fare ve sıçan gibi diğer memeli hücrelerinde DNA hasarına, mikroçekirdek ve DNA katım ürünü oluşumuna yol açarak genotoksik etki gös-terebileceği bildirilmiştir. 13,47,[49][50][51][52][53] OTA'nın temel toksik etki mekanizması, fenilalanine yapısal benzerliğinden dolayı, fenilanini substrat olarak kullanan birçok enzimi, özellikle fenilalanin-tRNA sentetazı inhibe ederek protein, DNA ve RNA sentezini inhibe etmesidir. 54 Ayrıca, ROT üretimini artırması ve lipit peroksidasyonunu artırarak hücre membranında hasar oluşturması da karsinojenik etkisi altında yatan diğer mekanizmalardır.…”

Section: Okratoksi̇nlerunclassified

Genotoxic Effects of Mycotoxins: Review

Beci̇t¹,

Aydın²,

Baydar³

2017

Turkiye Klinikleri J Pharm Sci

View full text Add to dashboard Cite

senobiyotiklere maruziyet sonucunda DNA'da meydana gelen kalıcı değişikliklere "mutasyon" denir. Mutasyon, genotoksik etkinin nihai bir sonucudur. DNA molekülünde oluşan başlıca primer DNA hasarları; DNA sarmalındaki tek ve çift iplik kırıklarını, DNA bazları ve proTurkiye Klinikleri J Pharm Sci 2017;6(2):59-76 59Mikotoksinlerin Genotoksik Etkileri Ö ÖZ ZE ET T Mikotoksinler, hem insan ve hayvan sağlığına olumsuz etkilere hem de ciddi ekonomik kayıplara neden olmaları açısından önemli riskler taşımaktadır. Mikotoksinlere maruziyet, asıl olarak kontamine yem ve gıdaların tüketilmesi ile olup, inhalasyon veya dermal yolla da temas söz konusu olabilmektedir. Mikotoksinler insan sağlığı üzerinde karaciğer, böbrek, bağışıklık, üreme ve gelişme sistemi gibi birçok organ ve sistemi olumsuz yönde etkileyebilmekte, düşük doz ancak kronik maruziyetlerinde özellikle genotoksik ve karsinojenik etkileri ile kansere yol açabilmektedir. Gı-dalarda önemli risk oluşturan mikotoksinler arasında Aspergillus, Penicillium, Fusarium ve Alternaria türlerinin oluşturduğu metabolitler yer almaktadır. Bu metabolitler arasında aflatoksinler, okratoksinler, zearalenon, trikotesenler, fusarium ve yeni keşfedilen fusarium mikotoksinler, patulin, alternaria toksinleri ve ergot alkaloitleri yer almaktadır. Günümüzde bazı mikotoksinlerin genotoksik olduğu artık bilinmektedir. Mikotoksinlerin genotoksik etki mekanizmalarına yönelik araştırmalar halen devam etmektedir. Her ne kadar in vitro çalışmalarda bazı mikotoksinlerin genotoksik etkileri gösterilmiş olsa da bu etkilerin in vivo koşullarla desteklenmesi, etki mekanizmalarının aydınlatılması ve epidemiyolojik çalışmalarla daha ileri değerlendirilmesi gerekmektedir. Bu derleme makalesinde, ekonomik kayıplara yol açan, toplum ve hayvan sağlığı için riskleri olan ve gıda kirleticileri olarak sık karşılaşılan mikotoksinlerin neden olduğu genetik hasarlardan ve bu hasarın olası mekanizmalarından bahsedilecektir.A An na ah h t ta ar r K Ke e l li i m me e l le er r: : Aflatoksinler; mutajenler; okratoksinler; mikotoksinler; patulin; mutajenlik testleri; fusarium; alternaria; ergotamin A AB BS S T TR RA AC CT T Mycotoxins have significant risks in terms of their adverse effects on human and animal health and causing serious economic losses. Exposure to mycotoxins is primarily through the consumption of contaminant feed and food, which may be through the inhalation or dermal route. Mycotoxins can adversely affect many organs and systems such as liver, kidney, immune system, reproductive and developmental system on human health. In low dose but chronic exposures, especially it can cause cancer with genotoxic and carcinogenic effects. Mycotoxins reveal significant risks in terms of both adverse effects on human and animal health and serious economic loss. Mycotoxins, which have significant risks in food, include metabolites of Aspergillus, Penicillium, Fusarium and Alternaria species, These metabolites include aflatoxins, ochratoxins, zearalenone, tricothecenes, fusarium and emerged fusarium mycotoxins...

show abstract

Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression

Cited by 40 publications

References 45 publications

Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats

Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats

Low doses of ochratoxin A induce micronucleus formation and delay DNA repair in human lymphocytes

Genotoxic Effects of Mycotoxins: Review

Contact Info

Product

Resources

About