FAST BREAKING PAPERS - 2008

  Why do you think your paper is highly cited?

Our paper is highly cited because it is a recent review on ochratoxin A (OTA) and includes 504 references. OTA is a fungal toxin (mycotoxin) and is a concern for the food industry. Over the past 30 years, 31,684 references dealing with mycotoxins have been published, according to PubMed. Many researchers are interested in developing analytical techniques for detection of mycotoxins in food and in establishing their mechanism(s) of toxicity.

  Does it describe a new discovery, methodology, or synthesis of knowledge?

Our paper represents a synthesis of knowledge and is based on the publications of many researchers in the field. Also included in the review are recent findings from the Manderville and Pfohl-Leszkowicz laboratories dealing with DNA damage caused by OTA.

  Would you summarize the significance of your paper in layman's terms?

OTA is a fungal toxin that is present in grains, cereal, wine, beer, and other food products. It is a kidney carcinogen in male rats and causes a kidney disease in pigs. It may also be a cause of human kidney carcinogenesis.

In this review evidence is presented that supports the DNA-damaging activity of OTA. It is proposed that ochratoxin A undergoes metabolism in the body to form reactive intermediates that attach to the DNA bases. This generates a DNA adduct, which, in general, is known to contribute to human carcinogenesis.

Currently, a provisional tolerable weekly intake level of OTA has been set at 100 ng/kg body weight, as established by the Joint FAO/WHO Expert Committee on Food Additives in 2001, which uses kidney disease in pigs as an endpoint. However, the acceptable intake levels of OTA are debated because of the growing concern of OTA as a human carcinogen. The data published in our review suggests that DNA damage and carcinogenicity should be used to establish acceptable intake levels of OTA from human food sources.

  How did you become involved in this research, and were there any problems along the way?

I am a chemist and I was interested in establishing how OTA reacts with DNA. Published evidence suggested that OTA undergoes oxidation in the body to form DNA adducts, but no structural evidence was published. My laboratory examined the oxidative properties of OTA and characterized an adduct resulting from attachment of OTA to deoxyguanosine. This adduct has been used by my collaborator, Dr. Annie Pfohl-Leszkowicz of the Ecole Nationale Supérieur Agronomique in Toulouse, France, to determine whether it is formed in animal tissue.

Maintaining funding for this project has been a problem. Other researchers have been unable to detect DNA adduct formation by OTA, so a great deal of negative evidence for DNA adduction by OTA has been published. However, much of the negative evidence has been published by researchers at food companies, or researchers funded by food companies, so a conflict of interest may be present.

  Where do you see your research leading in the future?

Once we have established unequivocal evidence for DNA adduction by OTA in animal tissue, my laboratory will be carrying out experiments to determine the biological impact of the OTA-DNA adduct. This will involve the synthesis of a DNA strand containing the adduct. This strand can then be used as a substrate for DNA polymerase and DNA repair enzymes. Our laboratory will also seek to measure the mutagenicity of the OTA-DNA adduct in human cells through research collaboration. Structural studies of the OTA-DNA adduct in duplex DNA would then be carried out here at the University of Guelph.

  Do you foresee any social or political implications for your research?

The findings from our studies do indeed have social and political implications. OTA is present in human food products and it is not easily removed. Agencies that place acceptable intake levels for mycotoxins may have to assess our data to establish intake levels for OTA. If levels become more restrictive, this could become costly for the food industry. Because OTA is in cereal and grain products, people will want to know if it is safe to eat these products. The general public should be made aware that the levels in these products are extremely low and are well below the levels needed to induce carcinogenesis in animal models.

Dr. Richard A. Manderville
Associate Professor of Chemistry
Departments of Chemistry and Toxicology
University of Guelph
Guelph, Ontario, Canada