Renal Lesions Induced by Ochratoxin A Exposure in the F344 Rat

Abstract

Groups of 80 male and female F344 rats were exposed by gavage to ochratoxin A, a naturally occurring mycotoxin, at levels of 21, 70, and 210 micrograms/kg body weight for up to 2 years. Ochratoxin A induced non-neoplastic renal tubular epithelial changes consisting of cytoplasmic alteration, karyomegaly, degeneration, and cysts. Exposure-related renal tubular proliferative lesions included focal hyperplasia, tubular cell adenoma, and tubular cell carcinoma. Renal tubular cell adenoma occurred as early as 9 months in 1 high-dose male rat, and both adenomas and carcinomas were seen in males by 15 months. At the terminal sacrifice, renal tubular cell tumors were found in both male and female rats, but the response was more pronounced in the males. The incidence of renal tumors in the high-dose rats was the highest of any National Toxicology Program (NTP) study completed to date. In the high-dose males approximately one-third of the renal carcinomas developed metastases. This study demonstrates that ochratoxin A is a potent renal carcinogen in the F344 rat and suggests that contamination of feedstuff by this mycotoxin may pose a potential hazard to domestic animals and man.

Renal tumourigenesis in male rats in response to chronic dietary ochratoxin A

“…Some rather small carcinomas and a few adenomas were discovered in an early stage of proliferation. Unfortunately, direct anatomical comparison of the present tumours with those in the NTP (Boorman 1989, Boorman et al 1992) and other lifetime studies is constrained by a lack of available published data. The present time course of incidence of rats with a renal carcinoma (20%) was compared with that in the NTP study by means of Cox proportional-hazard regression (see Table I, Figure 3).…”

Strain‐specific mammary proliferative lesion development following lifetime oral administration of ochratoxin A in DA and Lewis rats

“…The incidence of renal tubular carcinoma in male rats (60%) was the highest incidence of renal cell carcinomas found in any of the NTP studies. 5 The carcinogenic mechanism of OTA has not been elucidated, and genotoxicity results are contradictory. Castegnaro et al 8 compared OTA-induced renal carcinogenicity and DNA adducts in DA and Lewis rats of both sexes and reported that formation of these adducts appears to be correlated with toxicity and carcinogenicity.…”

“…2 Long-term animal studies have been conducted in rats and mice, and carcinogenic potential was reported in these species. [3][4][5] An NTP study in rats 6 reported that OTA induced uncommon tubular adenomas and tubular cell carcinomas of the kidney and multiple fibroadenomas of the mammary glands; on the basis of these results, the NTP classified OTA as having clear evidence of carcinogenic activity.Patients in the Balkan area who suffer from BEN have the EM profile for DB. 1 Accordingly, DA and Lewis rats were selected on the basis of their metabolic profiles as PMs and EMs, respectively, for DB in liver.…”

The role of α2u-globulin in ochratoxin A induced renal toxicity and tumors in F344 rats

“…However, most recent preliminary experiments from two independent laboratories failed to reproduce the latter data and thus failed to confirm the reported genotoxic activity of OTA (Dietrich and Turesky, personal communication). A two year mouse and rat bioassay (Bendele et al, 1985;Boorman et al, 1992), however, demonstrated that OTA is a potent renal carcinogen. These studies, revealed also a pronounced sex and species difference in kidney tumor induction, i.e.…”

“…The incidence of renal carcinomas was 28%. Female rats, on the other hand, were approximately 10-fold less responsive although not refractive to renal tumor induction (Boorman et al, 1992). Although several studies have been carried out to elucidate the mechanism(s) involved in OTA induced nephrotoxicity and carcinogenicity, little is known about the mechanism(s) leading to the observed sex and species differences.…”