RESUMEN
A series of publications in the 1950s described a kidney disease in Bulgaria, the former Yugoslavia and Romania that became known as Balkan endemic nephropathy (BEN). The disease was qualified by World Health Organisation (WHO) experts as 'progressive and very gradually developing renal failure with insidious onset.... The last stage shows marked fibrosis...'. BEN is characterized by tubular degeneration, interstitial fibrosis and hyalinization of glomeruli accompanied by enzymuria and impaired renal function without nephrotic syndrome. Later, an association between BEN and tumours of the kidney pelvis and ureter was recognized, so that the problem of BEN became not only nephrological, but also oncological. There may also be an association with increased urinary bladder cancer incidence, although many confounding factors may interfere in the analysis of data for this organ. In view of the very intimate association between BEN and the urinary tract tumours (UTT), the term 'endemic uropathy' has been proposed. Several hypothesis concerning the aetiology of these diseases has been investigated, which include: predisposing genes factors, environmental factors (heavy metals, minerals, bacteria, leptospira, viruses, fungal toxins and, most recently, pliocene lignites). This paper reviews the different hypotheses about the aetiology of endemic uropathy and pays particular attention to the role of fungal toxins.
Asunto(s)
Nefropatía de los Balcanes/inducido químicamente , Micotoxinas/efectos adversos , Neoplasias Urológicas/inducido químicamente , Citrinina/efectos adversos , Humanos , Metales Pesados/efectos adversos , Ocratoxinas/efectos adversosRESUMEN
Mycotoxic nephropathy was induced in 18 young pigs by diets contaminated with strains of Aspergillus ochraceus containing ochratoxin A (OTA) and penicillic acid (PA) at levels corresponding to those naturally encountered in animal feeds in Bulgaria. Haematological and biochemical parameters, as well as the morphological and ultrastructural changes in various internal organs, and especially in the kidneys, were examined at different stages of development of the disease. A mottled surface of the kidneys was only seen in pigs exposed to a mouldy diet containing 180 ppb OTA for 3 months, but microscopic lesions, as well as changes in various haematological and biochemical parameters, were observed in all groups exposed to the same mouldy diet containing only 90 or 180 ppb OTA. Histological examination showed two types of change: degenerative changes affecting the epithelial cells of the proximal tubules, which predominated at the initial stage, and proliferative changes in the interstitium, which predominated at the later stage of the disease. Telangiectasis and lymph stasis were also seen, as well as degenerative changes in the capillary endothelium. The characteristic renal lesions were similar to those observed in spontaneous cases of mycotoxic porcine nephropathy in Bulgaria, but they were a little different from the classic Danish porcine nephropathy. The enhanced toxicity of OTA in our study may be due to a synergistic effect between OTA and PA or to some other unknown metabolites produced by the same ochratoxinogenic strains of A. ochraceus.
Asunto(s)
Aspergillus ochraceus/metabolismo , Enfermedades Renales/veterinaria , Micosis/veterinaria , Micotoxinas/toxicidad , Ocratoxinas/toxicidad , Ácido Penicílico/toxicidad , Enfermedades de los Porcinos/microbiología , Alimentación Animal/microbiología , Animales , Aspergillus ochraceus/patogenicidad , Bulgaria , Femenino , Histocitoquímica/veterinaria , Riñón/efectos de los fármacos , Riñón/ultraestructura , Enfermedades Renales/inducido químicamente , Enfermedades Renales/microbiología , Enfermedades Renales/patología , Masculino , Microscopía Electrónica/veterinaria , Micosis/metabolismo , Micosis/microbiología , Micotoxinas/sangre , Micotoxinas/orina , Ocratoxinas/sangre , Ocratoxinas/orina , Ácido Penicílico/sangre , Ácido Penicílico/orina , Organismos Libres de Patógenos Específicos , Estadísticas no Paramétricas , Porcinos , Enfermedades de los Porcinos/inducido químicamente , Enfermedades de los Porcinos/patologíaRESUMEN
The dietary citrinin (CT) intake of 19 persons living in highrisk "Balkan Endemic Nephropathy" areas in Bulgaria was studied. Over 4 weeks, volunteers collected aliquots of their daily meals. Weekly samples were homogenized and analysed for CT by enzyme immunoassay (detection limit: 1ng/g). CT was found at least once in the weekly diet of 11 persons, maximum levels were at 6 ng/g. Considering the total amount of food consumed, the weekly CT intake of several persons exceeded 10 microgram. The data suggest that people living in high-risk nephropathy areas are exposed to dietary CT at considerable levels.
RESUMEN
Ochratoxin A (OTA) is a mycotoxin which has been detected in foods of plant origin, in edible animal tissues, and in human sera, urine, and milk in many countries. OTA is nephrotoxic and carcinogenic in mice and rats and is suspected to play a key role in the etiology of Balkan endemic nephropathy and/or associated urinary tract tumors. In the present study, some early signs of genetic impairment, including the presence of DNA adducts in target tissues from the progeny of mice after administration of a single OTA dose during late pregnancy, have been investigated. By the 32P-postlabeling method, several characteristic DNA adducts with the same Rf values were detected in kidney and liver of both the OTA-treated mice and their progeny the fetus and the offspring. No adduct was found in tissues from control animals. Different adducts were most important in kidney and liver DNA and some were organ-specific. High levels of DNA adducts were detected in the kidneys of male progeny, whereas in the female progeny and the mothers they were detected almost exclusively in the liver. This result correlates well with the carcinogenicity in mice: the target organ for males is the kidney, while for females it is the liver. High levels of DNA adducts were also found in fetuses. These results provide evidence for a direct genotoxic action of OTA in the progeny through transplacental contamination, which constitutes a new serious health hazard of exposure to this toxin.
Asunto(s)
Aductos de ADN , Lactancia , Intercambio Materno-Fetal , Ocratoxinas/toxicidad , Efectos Tardíos de la Exposición Prenatal , Administración Oral , Animales , Animales Recién Nacidos , Animales Lactantes , Femenino , Feto/química , Feto/efectos de los fármacos , Contaminación de Alimentos , Riñón/química , Riñón/efectos de los fármacos , Riñón/embriología , Hígado/química , Hígado/efectos de los fármacos , Hígado/embriología , Masculino , Ratones , Ratones Endogámicos C57BL , Ocratoxinas/administración & dosificación , Ocratoxinas/farmacocinética , Especificidad de Órganos , EmbarazoRESUMEN
Ochratoxin A is suspected of being one of the etiological agents responsible for Balkan endemic nephropathy and the associated urinary tract tumours. Contamination of cereals by this mycotoxin has been found to be more frequent in areas of endemic nephropathy than in areas where the disease is absent. As ochratoxin A binds to serum albumin, it should be detectable in biological fluids from exposed populations. A survey was thus conducted to determine the occurrence of ochratoxin A in blood from people living in the endemic area who were either affected or unaffected by the two diseases and in blood from people living in control regions where these diseases do not occur. Blood samples were collected in 1984, 1986, 1989 and 1990. Ochratoxin A was found more frequently and at higher levels in blood from patients with Balkan endemic nephropathy and/or urinary tract tumours than in blood from unaffected people from endemic and control areas. These findings suggest further that ochratoxin A is involved in the etiology of the two diseases.
Asunto(s)
Nefropatía de los Balcanes/sangre , Ocratoxinas/sangre , Neoplasias Urológicas/sangre , Nefropatía de los Balcanes/inducido químicamente , Nefropatía de los Balcanes/epidemiología , Bulgaria/epidemiología , Análisis por Conglomerados , Contaminación de Alimentos , Humanos , Incidencia , Estilo de Vida , Ocratoxinas/efectos adversos , Neoplasias Urológicas/inducido químicamente , Neoplasias Urológicas/epidemiologíaRESUMEN
Ochratoxin A has been detected more frequently and at higher levels as a contaminant in staple food consumed by subjects affected by Balkan endemic nephropathy or urinary tract tumours in the Vratza district (Bulgaria) than in samples from control populations in and outside the endemic area. Serum from patients with Balkan endemic nephropathy also contained ochratoxin A more frequently and at higher levels than serum from controls. Metabolic phenotyping of subjects in the Vratza district with debrisoquine revealed a preponderance of extensive metabolizers among subjects at high risk for Balkan endemic nephropathy. In rats, ochratoxin A is metabolized to 4-hydroxyochratoxin A, and rat strains shown to be poor or extensive metabolizers of debrisoquine were also poor or extensive metabolizers of ochratoxin A. In order to determine whether the metabolic phenotype for debrisoquine also parallels that of ochratoxin A in humans, a sensitive method was developed for quantifying ochratoxin A and its 4-hydroxy metabolite in human urine. This method was subsequently used to analyse urine from subjects who had previously been phenotyped for debrisoquine. Ochratoxin A was detected more frequently and at higher levels in urine from members of families affected by Balkan endemic nephropathy than in samples taken from subjects in control areas. No 4-hydroxyochratoxin A was found in any of these samples (detection limit, 15 ng/l urine). On the basis of results from human studies and animal models, the role of genetic polymorphism in drug oxidation and disease susceptibility is discussed briefly.
Asunto(s)
Nefropatía de los Balcanes/orina , Ocratoxinas/orina , Neoplasias Urológicas/orina , Animales , Nefropatía de los Balcanes/inducido químicamente , Nefropatía de los Balcanes/epidemiología , Nefropatía de los Balcanes/genética , Biotransformación , Bulgaria/epidemiología , Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Susceptibilidad a Enfermedades/enzimología , Contaminación de Alimentos , Predisposición Genética a la Enfermedad , Humanos , Oxigenasas de Función Mixta/metabolismo , Ocratoxinas/efectos adversos , Fenotipo , Ratas/metabolismo , Especificidad de la Especie , Neoplasias Urológicas/inducido químicamente , Neoplasias Urológicas/epidemiologíaRESUMEN
The etiology of Balkan endemic nephropathy and urinary tract tumours in the rural population of the endemic regions remains unknown. As one hypothesis involves mycotoxins, a survey was carried out to investigate the possible involvement of the nephrotoxic mycotoxins ochratoxin A and citrinin. Recently, this survey was extended to screening for the presence of other mycotoxins--aflatoxins, citrinin, sterigmatocystin and zearalenone. A total of 524 samples of home-produced and home-stored beans and maize from the harvests of 1984, 1985, 1986, 1989 and 1990 were analysed. Ochratoxin A was found in samples from both endemic and nonendemic areas, but more of the samples from affected families were contaminated, and at higher levels, than those from unaffected households. Citrinin and aflatoxins B1 and G1 were also found more frequently in samples from endemic areas. These results support the theory that mycotoxins are involved in the etiology of Balkan endemic nephropathy and urinary tract tumours.
Asunto(s)
Nefropatía de los Balcanes/epidemiología , Contaminación de Alimentos , Micotoxinas/análisis , Ocratoxinas/análisis , Neoplasias Urológicas/epidemiología , Aflatoxinas/análisis , Nefropatía de los Balcanes/inducido químicamente , Bulgaria/epidemiología , Citrinina/análisis , Análisis por Conglomerados , Fabaceae/química , Análisis de los Alimentos , Humanos , Incidencia , Micotoxinas/efectos adversos , Ocratoxinas/efectos adversos , Plantas Medicinales , Neoplasias Urológicas/inducido químicamente , Zea mays/químicaRESUMEN
Ochratoxin A (OA), a mycotoxin which induces nephropathy and kidney tumours in rats and mice, is a contaminant of food consumed by a population with a high incidence of endemic nephropathy (EN). It was therefore tested in vitro for its ability to induce chromosomal aberrations in human peripheral lymphocytes in a small number of subjects, in the presence or absence of a kidney microsomal metabolic activation system. OA was found to induce aberrations on X chromosomes of similar types to those previously detected in lymphocytes from patients suffering from endemic nephropathy.
Asunto(s)
Aberraciones Cromosómicas , Ocratoxinas/toxicidad , Trisomía , Cromosoma X , Animales , Nefropatía de los Balcanes/etiología , Nefropatía de los Balcanes/genética , Biotransformación , Células Cultivadas , Bandeo Cromosómico , Femenino , Humanos , Cariotipificación , Riñón/metabolismo , Linfocitos , Microsomas/metabolismo , Ocratoxinas/metabolismo , RatasRESUMEN
In continuing the effort to provide further evidence for the hypothesis that ochratoxin A might be involved in the aetiology of Balkan endemic nephropathy and the associated urinary system tumours, a survey to determine the occurrence of ochratoxin A in human blood was conducted in affected and unaffected areas of Bulgaria, where both diseases are prevalent. Ochratoxin A, positive samples, were present more often in blood from affected patients and the contamination levels were generally higher.
Asunto(s)
Nefropatía de los Balcanes/sangre , Nefritis Intersticial/sangre , Ocratoxinas/sangre , Neoplasias Urológicas/sangre , Nefropatía de los Balcanes/etiología , Nefropatía de los Balcanes/genética , Humanos , Valores de Referencia , Neoplasias Urológicas/etiología , Neoplasias Urológicas/genética , YugoslaviaRESUMEN
In an effort to provide further evidence for the hypothesis that a mycotoxin is involved in the aetiology of Balkan endemic nephropathy and that the latter is associated with the occurrence of urinary system tumours, a survey was made of ochratoxin A contamination of cereal samples from an area of Bulgaria where both endemic nephropathy and urinary system tumours are prevalent and from non-endemic areas. In all, 130 samples of beans, maize and wheat flour were analysed. Ochratoxin A levels were 16.7% (25-27 micrograms/kg) in bean samples from the endemic area and 7.1% (25-50 micrograms/kg) in those from the control areas: in maize samples, the levels were 27.3% (25-35 micrograms/kg) and 9.0% (10-25 micrograms/kg), respectively.
Asunto(s)
Nefropatía de los Balcanes/inducido químicamente , Grano Comestible/análisis , Microbiología de Alimentos , Nefritis Intersticial/inducido químicamente , Ocratoxinas/análisis , Fabaceae/análisis , Harina/análisis , Humanos , Ocratoxinas/efectos adversos , Plantas Medicinales , Triticum/análisis , Zea mays/análisisRESUMEN
LDH isozymes were assayed by polyacrylamide gel electrophoresis in 6 long-term transplantable skin tumours in Syrian hamsters. The percentages of the M-subunits were as follows: in a slow growing fibrosarcoma with abortive differentiation and producing lung metastases -- 63.3; in two well differentiated squamous cell carcinomas with moderate growth -- 79.8 and 74.9; in a slow growing and metastasizing melanotic melanoma -- 67.7; in undifferentiated amelanotic and depigmented melanomas with very fat growth -- 72.8 and 77.4. Therefore no consistent relationship has emerged between histogenesis, growth rate, differentiation and metastases of the studied neoplasms from one side and their LDH isozyme pattern -- on the other.
Asunto(s)
L-Lactato Deshidrogenasa/metabolismo , Neoplasias Cutáneas/enzimología , Animales , Carcinoma de Células Escamosas/enzimología , Línea Celular , Cricetinae , Femenino , Fibrosarcoma/enzimología , Isoenzimas , Masculino , Melanoma/enzimología , Mesocricetus , Estadificación de Neoplasias , Trasplante de Neoplasias , Neoplasias Experimentales/enzimología , Neoplasias Cutáneas/patologíaRESUMEN
LDH isoenzymes were assayed by acrylamide disc electrophoresis in the following material: (a) cells from 4 transplantable hamster tumors; (b) cells from the same tumors cultured for 0, 4, 12 or 24 h as well as for 3, 7, 12 or 26 days; (c) tumors obtained after re-inoculation of cells cultured for 26 days. During the first days of culture, the cells retained LDH patterns similar to those of tumors in vivo. Then a progressive increase in the M/H ratio was observed in all cultures. This was followed by a complete disappearance of LDH 1,2,3. In the tumors appearing after re-inoculation of cultured cells, re-emergence of the patterns seen in the original tumors was noted. The mechanism of the observed changes remains hypothetical although an adaptive re-arrangement of gene activity controlling the production of M and H subunits and/or in vitro selection of clones with higher M/H ratio is postulated.
Asunto(s)
L-Lactato Deshidrogenasa/análisis , Neoplasias Experimentales/enzimología , Animales , Diferenciación Celular , Células Cultivadas , Cricetinae , Femenino , Isoenzimas , Masculino , Trasplante de Neoplasias , Neoplasias Experimentales/patología , Trasplante HomólogoRESUMEN
Lactate dehydrogeanse (LDH) isozymes in the epidermis and in transplantable epidermal carcinoma from Syrian hamsters were studied by polyacrilamide electrophoresis. A 5-band pattern with occasional loss of 1--2 anode fractions in certain tumor samples is typical. In the epidermis of 14 to 15-day-old foetuses, in the regenerating epidermis, and in tumor cells cathode of M subunits predominate, in particular the fifth fraction in the last two cases. In the epidermis from new born, 25-day-old (growing stage of the hairs) and 60 to 80-day-old (resting stage of the hairs) animals a relative increase of the H subunits is striking. These results reveal a foetal-like pattern of LDH isozymes in regenerating and tumorous epidermis, as has been observed in other isozymes and in other tissues.
Asunto(s)
Carcinoma de Células Escamosas/enzimología , L-Lactato Deshidrogenasa/aislamiento & purificación , Neoplasias Cutáneas/enzimología , Animales , Carcinoma de Células Escamosas/ultraestructura , Cricetinae , Epidermis/enzimología , Epidermis/ultraestructura , Femenino , Isoenzimas , Masculino , Neoplasias Cutáneas/ultraestructuraAsunto(s)
Nefritis Intersticial/epidemiología , Neoplasias Urogenitales/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Bulgaria , Femenino , Humanos , Neoplasias Renales/epidemiología , Pelvis Renal , Masculino , Persona de Mediana Edad , Nefritis Intersticial/complicaciones , Nefritis Intersticial/genética , Factores Sexuales , Neoplasias Ureterales/epidemiología , Neoplasias Urogenitales/complicaciones , Neoplasias Urogenitales/genéticaRESUMEN
In hyperendemic villages in the Vratza district of Bulgaria, 193 patients with urinary system tumors (UST) were diagnosed during 1965 to 1976. A tendency towards familial aggregation was revealed when the patients were compared with two groups of controls, namely, patients with tumors other than UST and healthy persons. Each control group consisted of 193 persons matched by sex, age, and place of birth. This tendency was observed in all relatives who lived together as well as in those related by blood. The probability of having relatives with UST was 2.5 times higher than could be expected as chance occurrence among UST patients than among the controls. The UST cases also had significantly more relatives with endemic nephropathy than did the controls. The familial clustering of both UST and nephropathy in the endemic region is considered another clue to their common etiology.
Asunto(s)
Enfermedades Renales/complicaciones , Neoplasias Urogenitales/genética , Bulgaria , Métodos Epidemiológicos , Femenino , Humanos , Enfermedades Renales/epidemiología , Enfermedades Renales/genética , Masculino , Neoplasias Urogenitales/epidemiología , Neoplasias Urogenitales/etiologíaRESUMEN
In villages with endemic nephropathy (EN) high incidence and mortality rates of some urinary system tumors are reported. Age-adjusted incidences of renal pelvic and ureteral neoplasms were 46/10(5) in females and 27/10(5) in males; for urinary bladder tumors these figures were 16/10(5) and 35/10(5). The frequency of parenchymal kidney tumors was similar to that reported for the country as a whole. An increased relative risk of developing urinary system tumors was observed in patients with EN and with advancing age (only in women). Smoking did not relate to the occurrence of these neoplasms. No tumors of the urinary system were found in the investigated farm and domestic animals from the endemic region.
Asunto(s)
Nefritis Intersticial/epidemiología , Neoplasias Urogenitales/epidemiología , Animales , Bulgaria , Femenino , Humanos , Neoplasias Renales/epidemiología , Pelvis Renal , Masculino , Mapas como Asunto , Riesgo , Población Rural , Fumar/complicaciones , Neoplasias Ureterales/epidemiología , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias Urogenitales/mortalidad , Neoplasias Urogenitales/veterinariaRESUMEN
One hundred and thirty-eight patients diagnosed for urinary system tumours (UST), 714 patients with endemic nephropathy (EN) and 55 cases of UST and EN combined, all from endemic villages of Vratza district, Bulgaria were investigated for their familial pattern and time of diagnosis compared with the age at diagnosis. There were 144 spouses among these patients and nearly half of them came from non-endemic families and villages. The familial pattern followed the size of the population found to be at greater risk, i.e. people 40-60 years old, in particular women. Among the investigated 91 pairs of parents and children and 166 pairs of siblings the mean diagnostic interval was shorter than the mean difference of age at diagnosis. Therefore the epidemiologic data provide support to the hypothesis that possibly environment plays a predominant role in the familial aggregation and in the etiology of UST and EN in the endemic region.
Asunto(s)
Nefritis/epidemiología , Neoplasias Urogenitales/epidemiología , Adulto , Bulgaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefritis/etiología , Nefritis Hereditaria , Neoplasias Urogenitales/etiología , Neoplasias Urogenitales/genéticaRESUMEN
A study of three families living in villages with endemic nephropathy (EN) in Vratza district, Bulgaria, revealed 9 members with urinary system tumors (UST), 7 with UST and EN, and 7 with EN. Most cases were registered from 1962 to 1976. The predominant form was transitional cell neoplasms of the kidney pelvis and ureter in patients 40-60 years old. In about 40% of the patients more than one site in the urinary system was involved. One ovarian carcinoma was also registered in these families during this period. Persons related by marriage and coming from nonendemic families and villages were also affected by both diseases. In other branches of the three families living in other households or villages, only one case of EN was found.