Sex differences in ochratoxin A nephrotoxicity: A molecular approach to the mechanism of action

The aim of this project was to study the molecular basis of the sex differences in Ochratoxin A (OTA) sensitivity. OTA is a secondary metabolite produced by different fungal species of the genera Aspergillus and Penicillium (mainly by A. ochraceus and P. verrucosum). This mycotoxin can contaminate a great variety of vegetal products, especially grains. OTA causes various toxic effects, such as nephrotoxicity, hepatotoxicity, immunosuppression, neurotoxicity and teratogenicity. However, the main issue concerning OTA effect is its carcinogenic potential in kidney, the target organ. OTA has been classified as reasonably anticipated to be a human carcinogen (NTP, 2016) and as a probable human carcinogen (IARC, 1993) based on sufficient evidence from studies in experimental animals but inadequate in humans; and it has been described as one of the most potent carcinogens in rodents (Lock and Hard, 2004). In addition, considerable sex and species differences regarding OTA toxicity have been described. Understanding OTA mode of action and providing the appropriate knowledge about their related toxicological issues in a sex specific manner is critical not only to effectively support the evidence based decision making in food safety but also to understand the molecular basis of sex differences in Toxicology and Pharmacology. In this study, the sex-dependent response of F344 rats after a repeated OTA oral administration for 7 (0.50 mg/kg bw) or 21 days (0.21 and 0.50 mg/kg bw) was evaluated. General toxicity, sex and thyroid hormones and histopathology were studied. OTA was quantified in plasma, kidney and liver by HPLC-FLD and the expression of kidney transporter families was studied by RT-qPCR. Finally, the impact of sex on OTA-induced whole gene transcriptominc expression was studied in order to determine the key events that might be involved in the early events of the carcinogenic process.