Abstract
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.
Highlights
Ochratoxin A (OTA) is a mycotoxin produced by species of Aspergillus and Penicillium that has long been studied as a nephrotoxin, immunotoxin, teratogen and carcinogen
OTA contamination of grain is the cause of mycotoxic porcine nephropathy (a.k.a., “Danish nephropathy”), a renal disease of swine that is an important cause of economic losses in the pork industry [4,5] and may be responsible for some cases of nephropathy and cancer in humans [2]
OTA is strongly implicated as the cause of Balkan endemic nephropathy (BEN), a fatal tubulointerstitial disease that is associated with renal atrophy [2,6,7] and that exhibits features similar to porcine nephropathy in Bulgaria [5,7]
Summary
Ochratoxin A (OTA) is a mycotoxin produced by species of Aspergillus and Penicillium that has long been studied as a nephrotoxin, immunotoxin, teratogen and carcinogen (for recent reviews see [1,2,3]). Several areas of the Balkans that are known to have high levels of OTA-contamination of food have recently experienced a marked increase in the incidence of testicular cancer. More direct evidence of a carcinogenic role for OTA in the testis was provided by Mantle and Nolan [13] These investigators administered 100 μg OTA as a daily dietary contaminant to 24 male Fischer rats for 35 weeks. OTA consumption causes adducts in liver, kidney and testicular DNA [15,16]. This research tests the hypothesis that in utero exposure to OTA causes adducts in testicular DNA and that these lesions are similar to those that can be produced in the kidney and testis by the consumption of OTA.
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