Ochratoxin A in Human Diseases

OTA was linked with an outbreak of porcine nephropathy in Scandinavian countries [291].

Subsequently, the still unproven hypothesis of the involvement of OTA in the development of the Balkan endemic nephropathy (BEN) was postulated. BEN is a familial, chronic, non-inflammatory tubulointerstitial disease with insidious onset and slow progression to terminal renal failure that was first described in Bulgaria, former Yugoslavia and Romania [292, 293].

It affects people that live in the alluvial deposits along the tributaries of the Danube river in Bosnia and Herzegovina, Croatia, Romania, Bulgaria as well as Serbia [86]. Thus, the main characteristics of BEN are not only its focused and limited geographical distribution, but also

its occurrence in farming households, and a high mortality due to uraemia. The disease usually affects adults in their fourth to fifth decade and leads to tubular atrophy, periglomerular fibrosis and cortical cysts, inevitably progressing to degenerative and necrotic renal epithelia, hyperplastic arteriopathy and end-stage renal failure in their sixth decade [86, 294, 295]. BEN is often accompanied by upper urinary tract urothelial cancer, which is extremely aggressive in nature, and in spite of its endemic incidence in Balkan areas a similar clinical entity has been described throughout Europe, Asia and North America [295-297]. The incidence of urinary tract tumours (UTT) has been found to be much higher in regions with endemic nephropathy than in other regions [297-299]. The accompanying functional deficits in the early stages of the disease, which begins without an acute episode, include increased urinary concentrations of glucose, proteins, leucine aminopeptidase and γ-glutamyl transferase, coupled with a decrease in serum cholesterol and protein concentration.

Creatinine clearance rates and urinary specific gravity are markedly reduced [68].

Studies on OTA involvement in the aetiology of BEN and UTT were performed in Bulgaria and Croatia, where the mycotoxin was measured in various commodities of plant and animal origin as well as in human blood [300-307]. In endemic regions high OTA blood concentrations were a frequent finding in patients with chronic renal insufficiency. However, low concentrations of OTA have frequently been detected both in the blood of people from non-endemic regions and in the blood of healthy inhabitants from other countries where endemic nephropathy does not occur (cited in [300]). Hence, it is still not possible to link the exposure to OTA to BEN and UTT.

While there is a general agreement in the scientific literature that at least one environmental toxin must be involved, the responsible agent has still not been identified. It has been proposed that materials derived from the plant Aristolochia clematitis and related species as well as mycotoxins such as OTA might play a role in the outbreak of BEN and UTT [308]. A third hypothesis, the Pliocene lignite hypothesis, proposes that a long-term exposure to polycyclic aromatic hydrocarbons and other toxic organic compounds, which leak into the well drinking water from low-rank coals in the vicinity of the endemic settlements, is responsible for the onset of BEN [309-311]. At an international symposium held in Zagreb (Croatia) in 2006 Grollman and Jelakovic favoured the long-term exposure to aristolochic acid (AA) as the cause for BEN [296]. At the same symposium, Long et al. postulated that neither OTA nor AA can be firmly linked to Balkan endemic nephropathy [312]. Their

analysis revealed environmental and health sciences issues that need to be adressed in order to understand the role of OTA and/or AA in the etiology of BEN. In contrast, Pfohl-Leszkowicz et al. recently reported on a comparative investigation of the mycotoxins OTA and citrinin (CIT) as well as AA and highlighted the implication of OTA and CIT in BEN and UTT, whereas AA derivatives were not implicated either in BEN or in slimming regimens [294].

Nikolic et al. demonstrated that the very intimate link between BEN and UTT can be explained by the insult induced by an environmental contaminant [313]. The intake of the agent at high doses causes nephropathy and early appearance of renal failure (BEN) during the third and the fourth decade of a patient’s life. Moreover, at low doses of the potential causative agent, the nephropathy is not recognised, but UTT still develops. Under these conditions, the patient may die from UTT even though kidney damage is minimal and subclinical, so that most of the patients (75 %) in a BEN settlement may show no symptoms of renal failure at the time of nephrectomy.

Interestingly, BEN rather affects people living in rural areas but not those living in towns in the vicinity [93]. This could be explained by the fact that rural populations consume more home-grown and home-stored food, whereas city dwellers consume predominantly commercially available and industrially produced food. The disease often affects many members of one family, while neighbouring families may be free from the disease over several generations. This may be due to the family’s dietary habits as well as conditions of food storage and, consequently, conditions promoting mould contamination and growing.

The predominant occurrence of BEN in specific families suggested that a genetic predisposition may also be involved. Toncheva et al. proposed that alterations in the gene coding for transforming growth factor-β (TGF-β), the genetic heterogeneity of xenobiotic-metabolising enzymes or defects in the immune system of the host could predispose to BEN [315]. Recently, genetic polymorphisms of some xenobiotic-metabolising enzymes have been associated with BEN [314-317]. Genetic variants of enzymes involved in the uptake, biotransformation and elimination of xenobiotics determine individual levels of detoxification and are modifiers of an increased/decreased risk for chronic diseases and cancer. Furthermore, genetic alterations predisposing BEN patients to UTT could be germline mutations in tumour-suppressor genes and/or acquired somatic mutations in oncogenes [318]. Genetic

polymorphisms related to specific transporters may also contribute to inter-individual differences in the response to environmental toxins such as OTA [316, 319, 320].