Persistent karyomegaly caused byPenicilliumnephrotoxins in the rat

Abstract

Continuous or intermittent consumption by rats of food moulded by Penicillium aurantiogriseum induced prominent and extensive histopathological changes within several weeks seen specifically at the renal cortico-medullary junction. Many cells of the P3 segment of proximal tubules contained either giant nuclei or multiple enlarged nuclei, described in this text as karyomegaly, but also included within a cytomegalic change. The changes contrasted with the tubular cell necrosis and concomitant mitosis elicited after only four days consumption of nephrotoxic mould. Unilateral nephrectomy enabled persistence of histopathological changes to be assessed directly after detailed histology at an earlier stage. After ten days consumption of food with a 100-fold excess of fungal extract containing the amphoteric nephrotoxins, the typical acute histopathology evolved, over a period of three weeks on normal diet, into the bizarre karyomegalic histopathology, implying a latent effect. Karyomegaly persisted for at least twelve months after nephrotoxin dosage ceased. P. aurantiogriseum karyomegaly was much more striking than that induced by a relatively high chronic dose of another Penicillium nephrotoxin, ochratoxin A. Although the study does not attempt to measure relative potencies, qualitatively similar ultrastructural changes (enlarged nuclei, proliferation of smooth endoplasmic reticulum and thickening of proximal tubule basement membranes) were induced by the two types of nephrotoxin. The broadly toxic ochratoxin A is the popular putative aetiological agent in the mysterious and insidious Balkan endemic nephropathy and associated urinary tract tumours. As the renal carcinogenicity of ochratoxin A in rats follows karyomegaly, the striking karyomegaly induced by P. aurantiogriseum in the proximal tubules of the kidney must be considered as a potential factor in human chronic renal disease.

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

“…The changes included karyomegaly and exfoliation of single cells, oncotic and/or apoptotic necrosis (Majno and Joris, 1996;Levin, 1998) and increased regeneration of single cells as well as of whole tubules (Figs. 1 and 2), corroborating histopathological changes observed previously in the proxima of rats following chronic treatment with OTA (Mantle et al, 1991). Similar pathological changes were reported by Heussner et al (1998) in primary rat cortex and distal kidney cells as well as in LLC-PK1 cells and by Seegers and coworkers (Seegers et al, 1994) in hamster kidney cells exposed to moderate to high OTA concentrations (10 − 7 -5× 10 − 5 M) in vitro.…”

Ochratoxine A et néphropathie humaine en Tunisie : dix ans d'étude

“…Des études ont montré que l'OTA induit des adénomes rénaux chez la souris et chez le rat (14,15) ; de plus, l'OTA apparaît comme la cause principale de la néphrotoxicité porcine spontanée et de néphropathie chez les volailles (16,17).…”

Renal Histopathological Responses to Nephrotoxic <i>Penicillium aurantiogriseum</i> in the Rat during Pregnancy, Lactation and after Weaning

“…I) commencing with 2 Sprague-Dawley virgin female rats mated concurrently. One rat (A) was fed from the day after mating until, and including, the day before parturition on a powdered rat breeder diet (initially 25 g daily) containing, notionally, 20% of shredded wheat moulded with nephrotoxic P. aurantiogriseum as previously described [7], The mouldy shredded wheat was blended directly into powdered rat diet moistened with vegetable oil to bind the powdery spore component. The amounts of nephrotoxic component ingested, quoted in figures I and 2, are the weight of shredded wheat before moulding by P. aurantiogriseum.…”

“…The apparently organ-specific renal histopathological responses have re cently been differentiated into distinct acute and chronic changes [6][7][8]. Both the acute pyknosis and mitosis in proxi mal tubules and the chronically-induced persistent ka ryomegaly in the same region of nephrons have been shown to be much more prominent than that induced by the important nephrotoxic mycotoxin ochratoxin A when the latter was given at a fairly high dose.…”

“…Both the acute pyknosis and mitosis in proxi mal tubules and the chronically-induced persistent ka ryomegaly in the same region of nephrons have been shown to be much more prominent than that induced by the important nephrotoxic mycotoxin ochratoxin A when the latter was given at a fairly high dose. Although P. aurantioAccepted : March 12.1993 griseum nephrotoxins have only been partially charac terized [7], both types of nephrotoxin command interest at least as models of pathogenesis in research on the idiopath ic human disease Balkan endemic nephropathy with which is associated a high incidence of urothelial tumours [9], The rapidity of a renal histopathological response to nephro toxic P. aurantiogriseum in adult rats [6] allows expectation that a pilot study of renal responses during stages in repro duction and after weaning could enable experimental pa thology to be followed during these relatively short periods. Such study could make a meaningful prelude to a direct comparison with the important nephrotoxin ochratoxin A, some analogous aspects of the nephrotoxicity of which have been neglected.…”