This review discusses mechanisms of toxicity, particularly those observed in liver tissue, mediated by microcystins (MCs) produced by cyanobacteria.

Ochratoxin A (OTA) is a para-chlorophenolic mycotoxin produced by strains of Aspergillus and Penicillium that is widely found as a contaminant of improperly stored food products. The toxin is a potent renal carcinogen in rats, especially male, and has an implicated role in the etiology of Balkan endemic nephropathy and its associated urinary tract tumours. Although the mechanism of OTA-mediated tumour formation is not fully understood, and represents a hotly debated topic, bioactivation and subsequent DNA adduction through covalent attachment of electrophilic OTA species remains a viable mechanism for OTA-mediated carcinogenesis. In this paper we outline the established chemistry for the bioactivation of chlorophenol carcinogens and demonstrate how this chemistry relates to the bioactivation of OTA. From this basis it is predicted that OTA will form a benzoquinone electrophile following activation by cytochrome P450 enzymes and radical species following activation by enzymes with peroxidase activities. These electrophiles react preferentially with deoxyguanosine (dG) to form benzetheno adducts and C8- dG adducts, respectively. Analysis of OTA-mediated DNA adduction using the ³²P-postlabelling method correlates with OTA chemistry and adduct spots derived from the quinone electrophile are generated following activation by cytochrome P450, while a C8-OTA adduct is formed following activation of OTA by peroxidase enzymes. These same adduct spots are also produced in animal (rat and pig) and human tumoral kidney tissue. This model for OTAmediated carcinogenesis is consistent with established structure-activity relationships for covalent attachment of OTA analogues and OTA toxicity. The model also provides a rationale for the synergistic effect observed for OTA in the presence of the mycotoxin citrinin and for the sexual differences observed in rat carcinogenesis where the male is particularly susceptible to OTA-mediated tumour formation.

Ochratoxin A (OTA) is a nephrotoxin and carcinogen that is associated with Balkan endemic nephropathy and urinary tract tumors. OTA crosses the placenta and causes adducts in the liver and kidney DNA of newborns. Because the testis and kidney develop from the same embryonic tissue, we reasoned that OTA also may cause adducts transplacentally in the testis. We tested the hypothesis that acute exposure to OTA, via food and via exposure in utero, causes adducts in testicular DNA and that these lesions are identical to those that can be produced in the kidney and testis by the consumption of OTA. Adult mice received a single dose of OTA (from 0–1,056 µg/kg) by gavage. Pregnant mice received a single i.p. injection of OTA (2.5 mg/kg) at gestation day 17. DNA adducts were determined by ³²P-postlabeling. Gavage-fed animals sacrificed after 48 hours accumulated OTA in kidney and testis and showed DNA adducts in kidney and testis. Some OTA metabolites isolated from the tissues were similar in both organs (kidney and testis). The litters of mice exposed prenatally to OTA showed no signs of overt toxicity. However, newborn and 1-month old males had DNA adducts in kidney and testis that were chromatographically similar to DNA adducts observed in the kidney and testis of gavage-fed adults. One adduct was identified previously as C8-dG-OTA adduct by LC MS/MS. No adducts were observed in males from dams not exposed to OTA. Our findings that in utero exposure to OTA causes adducts in the testicular DNA of male offspring support a possible role for OTA in testicular cancer.