Abstract
Little is known about the etiology of testicular cancer, which is the most common cancer among young men. Epidemiologic data point to a carcinogenic exposure in early life or in utero, but the nature of the exposure is unknown. We hypothesize that the mycotoxin, ochratoxin A, is a cause of testicular cancer. Ochratoxin A is a naturally occurring contaminant of cereals, pigmeat, and other foods and is a known genotoxic carcinogen in animals. The major features of the descriptive epidemiology of testicular cancer (a high incidence in northern Europe, increasing incidence over time, and associations with high socioeconomic status, and with poor semen quality) are all associated with exposure to ochratoxin A. Exposure of animals to ochratoxin A via the diet or via in utero transfer induces adducts in testicular DNA. We hypothesize that consumption of foods contaminated with ochratoxin A during pregnancy and/or childhood induces lesions in testicular DNA and that puberty promotes these lesions to testicular cancer. We tested the ochratoxin A hypothesis using ecologic data on the per-capita consumption of cereals, coffee, and pigmeat, the principal dietary sources of ochratoxin A. Incidence rates for testicular cancer in 20 countries were significantly correlated with the per-capita consumption of coffee and pigmeat (r = 0.49 and 0.54, p = 0.03 and 0.01). The ochratoxin A hypothesis offers a coherent explanation for much of the descriptive epidemiology of testicular cancer and suggests new avenues for analytic research.
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References
Buetow SA (1995) Epidemiology of testicular cancer. Epidemiol Rev 17: 433-449.
Schottenfeld D (1996) Testicular cancer. In: Schottenfeld D, fraåmeni JF Jr. eds. Cancer Epidemiology and Prevention, 2nd edn., New York: Oxford University Press, pp. 1207-1219.
Møller H (1993) Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur Urol 23: 8-15.
Jensen OM, Esteve J, Møller H, Renard H (1990) Cancer in the European community and its member states. Eur J Cancer 26: 1167-1256.
Adami H-O, Bergstro¨ m R, Mo¨ hner M, et al. (1994) Testicular cancer in nine northern European countries. Int J Cancer 59: 33-38.
Ekbom A (1998) Growing evidence that severalhuman cancers may originate in utero. Sem. Cancer Biol 8: 237-244.
Chivers C, Pike MC (1992) Cancer risk in the undescended testicle. Eur Urol Update Series 1: 74-79.
Møller H, Prener A, Skakkebæk NE (1996) Testicular cancer, cryptorchidism, inguinalhernia, testicular atrophy, and genital malformations: case-control studies in Denmark. Cancer Causes Control 7: 264-274.
Jacobsen R, Bostofte E, Engholm G, et al. (2000) Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ 321: 789-792.
Sharpe RM, Skakkebæk NE (1993) Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 341: 1392-1395.
Petersen PM, Skakkebæk NE, Giwercman A (1998) Gonadal function in men with testicular cancer: biological and clinical aspects. APMIS 106: 24-36.
Davies JM (1981) Testicular cancer in England and Wales: some epidemiologic aspects. Lancet 1: 928-932.
Ross RK, McCurtis JW, Henderson BE, Menck HR, Mack TM, Martin SP (1979) Descriptive epidemiology of testicular and prostatic cancer in Los Angeles. Br J Cancer 39: 284-292.
Swerdlow AJ, Skeet RG (1985) Occupational associations of testicular cancer in south east England. Br J Ind Med 45: 225-230.
Forman D, Møller H (1994) Testicular cancer. Cancer Surv Trends Cancer Incid Mort 19/20: 323-341.
Petersen GR, Lee JAH (1972) Secular trends of malignant tumors of the testis in white men. J Natl Cancer Inst 49: 339-354.
Bergstro¨ m R, Adami HO, Mo¨ hner M, et al. (1996) Increase in testicular cancer in six European countries: A birth cohort phenomenon. J Natl Cancer Inst 88: 727-733.
Swerdlow AJ, Huttly SR, Smith PG (1987) Prenatal and familial associations of testicular cancer. Br J Cancer 55: 571-577.
Henderson BE, Benton B, Jing J, Mimi CY, Pike MC (1979) Risk factors for cancer of the testis in young men. Int J Cancer 23: 598-602.
Toppari J, Larsen JC, Christiansen P, et al. (1996) Male reproductive health and environmental xenoestrogens. Env Health Perspect: 104 (Suppl. 4): 741-803.
Rajpert-De Meyts E, Skakkebæk NE (1993) The possible role of sex hormones in the development of testicular cancer. Eur Urol 23: 54-61.
Brown LM, Pottern LM, Hoover RN (1987) Testicular cancer in young men: the search for causes of the epidemic increase in the United States. J Epidemiol Commun Health 41: 349-354.
Akre O, Lipworth L, Tretli S, et al. (1999) Epstein-Barr virus and cytomegalovirus in relation to testicular-cancer risk: a nested case-controlstudy. Int J Cancer 82: 1-5.
Forman D, Gallagher R, Møller H, Swerdlow TJ (1990) Aetiology and epidemiology of testicular cancer: report of consensus group. EORTC Genitourinary Group Monograph 7: 245-253.
Swerdlow AJ (1993) The epidemiology of testicular cancer. Eur Urol 23: (Suppl. 2): 35-38.
Pitt JI (2000) Toxigenic fungi and mycotoxins. Br Med Bull 56: 184-192.
Abramson D, Richeter W, Rintelen J, Sinha RN, Schuster M (1992) Ochratoxin A production in Bavarian cerealgrains stored at 15 and 19% moisture content. Arch Environ Contam Toxicol 23: 259-265.
Lillehoj H, Elling F (1983) Environmental conditions that facilitate ochratoxin contamination of agricultural commodities. Acta Agric Scand 33: 113-128.
Kuiper-Goodman T, Scott PM (1989) Risk assessment of the mycotoxin ochratoxin A. Biomed Environ Sci 2: 179-248.
InternationalAgency for Research on Cancer (1993) IARC Monographs on the Evaluation of Carcinogenic Risks to Human. Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins. Lyon, vol. 56.
Pohland AE, Nesheim S, Friedman L (1992) Ochratoxin A: a review. Pure Appl Chem 64: 1029-1048.
Petzinger E, Zeigler K (2000) Ochratoxin A from a toxicologic perspective. J Vet Pharmacol Ther 23: 91-98.
Marquardt RR, Frohlich AA (1992) A review of recent advances in understanding ochratoxicosis. J Anim Sci 70: 3968-3988.
Diekman MA, Green ML (1992) Mycotoxins and reproduction in domestic livestock. J Anim Sci 70: 1615-1627.
Commission of the European Communities (1996) Reports on tasks for scientific cooperation. Report of experts participating in task 3.2.2: assessment of dietary intake of ochratoxin A by the population in EU member states. Report EUR 17523 EN. 98 G.G. Schwartz
Nordic Working Groups on Food Toxicology and Risk Evaluation (1991) Health evaluation of ochratoxin A in food products. Nordiske Seminar-Og Arbejdsrapporter. Government Report, Nordic Councilof Ministers, Copenhagen, 545, 1-26.
Wood GE (1992) Mycotoxins in foods and feeds in the United States. J Anim Sci 70: 3941-3949.
Truckseee MW, Giler J, Young K, White KD, Page SW (1999) Determination and survey of ochratoxin A in wheat, barley, and coffee-1997. J AOAC Int 82: 85-89.
Bauer J, Gareis M (1987) Ochratoxin A in the food chain. Z Veterinarmed [B] 34: 613-627 [in German].
Frohlich AA, Marquardt RR, Ominiski KH (1991) Ochratoxin A as a contaminant in the human food chain: A Canadian perspective. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IM, Bartsch H, eds. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours. Lyon: IARC Scientific Publication No. 115. New York: Oxford University Press, pp. 139-143.
Larsen S (1928) On chronic degeneration of the kidneys caused by mouldy rye. Maanedsskr Dyrl 40: 259-294, 289-300 [in Danish].
Krogh P (1976) Epidemiology of mycotoxic porcine nephropathy. Nord Vet-Med 28: 452-458.
Čeovic´ S, Pleština R, Miletic´-Medved M, Stavljenic´ A, Mitar J, Vukelic´ M (1991) Epidemiological aspects of Balkan endemic nephropathy in a typicalfocus in Yugoslavia. In: Castegnaro M, Peština R, Dirheimer G, Chernozemsky IM, Bartsch H, eds. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours. Lyon: IARC Scientific Publication No. 115. New York: Oxford University Press, pp. 5-10.
Radovanic´ Z, Jankovic´ S, Jeremovic´ I (1991) Incidence of tumors of urinary origin in a focus of Balkan endemic nephropathy. Kidney Int Suppl34: S75-S76.
Tatu CA, Orem WH, Finkelman RB, Feder GL (1998) The etiology of Balkan endemic nephropathy: still more questions than answers. Env Health Perspect 106: 689-700.
Boorman G, ed. (1989) NTP Technical Report on the Toxicology and Carcinogenesis Studies of Ochratoxin A. NIH Publication No. 89-2813. US Department of Health and Human Services, NIH, Research Triangle Park, NC.
Pfohl-Leszkowicz A, Grosse Y, Kane A, Creppy EE, Dirheimer G (1993) DifferentialDNA adduct formation and disappearance in three mice tissues after treatment by the mycotoxin, ochratoxin A. Mutat Res 289: 265-273.
Petkova-Bocharova T, Stoichev II, Chernozemsky IN, Castergnaro M, Pfohl-Leszkowicz A (1998) Formation of DNA adducts in tissues of mouse progeny through transplacental contamination and/or lactation after administration of a single dose of ochratoxin A to the pregnant mother. Environ Mol Mutagen 32: 155-162.
Ho¨ hler D (1998) Ochratoxin A in food and feed: Occurrence, legislation, and mode of action. Z Erna¨hrungswiss 37: 2-12.
fraåk HK (1991) Risk estimation for ochratoxin A in European countries. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H, eds. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours. Lyon: IARC Scientific Publication No. 115. New York: Oxford University Press, pp. 321-325.
Hald B (1991) Ochratoxin A in human blood in European countries. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H, eds. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours. Lyon: IARC Scientific Publication No. 115. New York: Oxford University press, pp. 159-164.
Scheuer R (1989) Untersuchungen zum Vorkommen von Ochratoxin A. Fleischwirtschaft 69: 1400-1404.
Weile B, Cavell B, Nivenius K, Krasilnikoff PA (1996) Striking differences in the incidence of childhood celiac disease between Denmark and Sweden: a plausible explanation. J Pediatr Gastroenterol Nutr 21: 64-68.
Ascher H, Holm K, Dristiansson B, Ma¨ ki M (1993) Different features of coeliac disease in two neighbouring countries. Arch Dis Child 69: 375-380.
Rosegrant MW, Leach N, Gerpacio RV (1999) ''Meat or wheat for the next millennium?''. Plenary Lecture. Alternative futures for world cereal and meat consumption. Proc Nutr Soc 58: 219-234.
Trygg J (1991) Food patterns in the Nordic countries. Ann Nutr Metab 35 (Suppl. 1): 3-11.
Hill C (1990) Overview of available data on diet and cancer mortality in fraåce. Tumori 31: 299-305.
Strøm A (1948) Examination into the diet of Norwegian families during the war-years 1942-1945. Acta Med Scand 214 (Suppl.): 3-47.
Willett WC (1998) Dietary fat intake and cancer risk: a controversialand instructive story. Sem Cancer Biol 8: 245-253.
Skaug MA, Helland I, Solvoll K, Saugstad OD (2001) Presence of ochratoxin A in human milk in relation to dietary intake. Food Add Contam 18: 321-327.
Breitoltz-Emanuelsson A, Olsen M, Oskarsson A, Palminger I, Hult K (1993) Ochratoxin A in cow's milk and in human milk with corresponding human blood samples. J AOAC Int 76: 842-846.
Skaug MA, Stormer FC, Saugstad OD (1998) Ochratoxin A: a naturally occurring mycotoxin found in human milk samples from Norway. Acta Pædiatr 87: 1275-1278.
Scott JA, Binns CW (1999) Factors associated with the initiation and duration of breastfeeding: a review of the literature. Breastfeed Rev 7: 5-16.
Michaelsen KF, Larsen PS, Thomsen BL, Samuelson G (1994) The Copenhagen cohort study on infant nutrition and growth: duration of breast feeding and influencing factors. Acta Paediatr 83: 565-571.
Møller H, Skakkebæk NE (1996) Risks of testicular cancer and cryptorchidism in relation to socio-economic status and related factors: case-controlstudies in Denmark. Int J Cancer 66: 287-293.
Fenske M, Fink-Gremmels J (1990) Effects of fungal metabolites on testosterone secretion in vitro. Arch Toxicol 64: 72-75.
More J, Camguilhem R (1979) Effects of low doses of ochratoxin A after intratesticular injection in the rat. Experientia 35: 890-892.
Solti L, Pecs T, Betro-Barna I, Szasz F Jr, Biro K, Azabo E (1999) Analysis of serum and seminal plasma after feeding ochratxoin A with breeding boars. Anim Reprod Sci 28: 123-132.
Gharbi A, Trillon O, Betbeder AM, et al. (1993) Some effects of ochratoxin A, a mycotoxin contaminating feeds and food, on rat testis. Toxicology 83: 9-18.
Bose S, Sinha SP (1994) Modulation of ochratoxin-produced genotoxicity in mice by vitamin C. Food Chem Toxicol 32: 533-537.
Kazanas N, Ely RW, Fields ML, Erdman JW Jr (1984) Toxic effects of fermented and unfermented sorghum mealdiets naturally contaminated with mycotoxins. Appl Environ Microbiol 47: 1118-1125.
Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J (1997) Cancer Incidence in Five Continents, vol. VII. Lyon: IARC Scientific Publications No. 143.
Food and Agricultural Organization of the United Nations (1984) Food Balance Sheets, 1979-81, Average. Rome, 1984. Ochratoxin A and testicular cancer 99
Binstock M, Krakow D, Stamler J, Reiff J, Persky V, Liu K, Moss D (1983) Coffee and pancreatic cancer: an analysis of internationalmortal ity data. Am J Epidemiol 118: 630-640.
Galal OM (1998) Uses of food consumption data: with an example exploring the impact of food consumption on economic growth. Public Health Rev 26: 109-122.
vd Stegen G, Jorissen U, Pittet A, et al. (1997) Screening of European coffee finalproduct s for occurrence of ochratoxin A (OTA). Food Addit Contam 14: 211-216.
Jørgensen K (1998) Survey of pork, poultry, coffee, beer and pulses for ochratoxin A. Food Addit Contam 15: 550-554.
Bernarde MA, Weiss W (1982) Coffee consumption and pancreatic cancer: temporaland spatial correlation. BMJ 284: 400-402.
Morgenstern H (1995) Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Publ Health 16: 61-81.
Fuchs R, Appelgran LE, Hutt K (1988) Distribution of 14C-ochratoxin A in the mouse monitored by whole-body autoradiography. Pharmacol Toxicol 63: 355-360.
Galtier P, Charpenteau J-L, Alvinerie M, Labouche C (1979) The pharmacokinetic profile of ochratoxin A in the rat after oral and intravenous administration. Drug Metab Distribut 7: 429-434.
Fukai YC, Hoshino K, Kameyama T, Yasui T, Toda C, Nagiono H (1987) Placental transfer of ochratoxin A and its cytotoxic effect on the mouse embryonic brain. Food Chem Toxicol 25: 17-24.
Ballinger MB, Phillips TE, Kubena LF (1986) Assessment of the distribution and elimination of ochratoxin A in the pregnant rat. J Food Safety 8: 11-24.
Barnikol H, Thalmann A (1988) Klinische Beobachtungen beim Schwein in Zusammenhang mit den Mykotoxinen Ochratoxin A und Zearalenon. Tiera¨rztl Umsch 43: 74-82.
Jonsyn FE, Maxwell SM, Hendrickse RG (1995) Human fetal exposure to ochratoxin A and aflatoxins. Ann Trop Paediatr 15: 3-9.
Zimmerli B, Dick R (1995) Determination of ochratoxin A at the ppt level in human blood, serum, milk and some foodstuffs by high-performance liquid chromatography with enhanced fluorescence detection and immunoaffinity column cleanup: methodology and Swiss data. J Chromat B Biomed Appl 666: 85-99.
Ferrufino-Guardia EV, Tangni EK, Larondelle Y, Ponchaut S (2000) Transfer of ochratoxin A during lactation: exposure of suckling via the milk of rabbit does fed a naturally-contaminated feed. Food Addit Contam 17: 167-175.
Halle` nm IP, Breitholtz-Emanuelsson A, Hult K, Olsen M, Oskarsson A (1998) Placental and lactational transfer of ochratoxin A in rats. Nat Toxins 6: 43-49.
Kane A, Creppy EE, Roth A, Ro¨ schenhaler R, Dirheimer G(1986) Distribution of the [3H]-label from low doses of radioactive ochratoxin A ingested by rats, and evidence from DNA singlestrand breaks caused in liver and kidneys. Arch Toxicol 58: 219-224.
Kanisawa M, Suzuki S (1978) Induction of renaland hepatic tumors in mice by ochratoxin A, a mycotoxin. Gann 69: 599-600.
Bendele AM, Carlton WW, Krogh P, Lillehoj EB (1985) Ochratoxin A carcinogenesis in the (C57BL/6J · C3H)F1 mouse. J Natl Cancer Inst 75: 733-742.
Lutz WK, Gaylor D (1996) Significance of DNA adducts at low dose: shortening the time to spontaneous tumor occurrence. Regul Toxicol Pharmacol 23: 29-34.
Poirior MC, Beland FA (1992) DNA adduct measurements and tumor incidence during chronic carcinogen exposure in animal models: implications for DNA adduct-based human cancer risk assessment. Chem Res Toxicol 5: 749-755.
Castegnaro M, Mohr U, Pfohl-Leszkowicz A, et al. (1998) Sexand strain-specific induction of renaltumors by ochratoxin A in rats correlates with DNA adduction. Int J Cancer 77: 70-75.
Rørth M, Rajpert-De Meyts E, Andersson L, et al. (2000) Carcinoma in situ in the testis. Scand J Urol Nephrol Suppl205: 166-186.
Drew RT, Boorman GA, Haseman JK, McConnel EE, Busey WM, Moore JA (1983) The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol Appl Pharmacol 68: 120-130.
Cortes D, Thorup JM, Beck BL (1995) Quantitative histology of germ cells in the undescended testes in human fetuses, neonates and infants. J Urol 154: 1188-1192.
Cortes D, Thorup JM, Beck BL, Visfeldt J (1998) Cryptorchidism as a causal developmental field defect. APMIS 106: 953-958.
Padmanabhan R, Naruse I, Shiota K (1999) Caudaldysgene sis in staged human embryos: Carnegie stages 16-23. Am J Med Genet 87: 115-127.
Wei X, Sulik KK (1996) Pathogenesis of caudal dysgenesis/ sirenomelia induced by ochratoxin A in chick embryos. Teratology 53: 378-391.
Paulozzi LJ (1999) International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect 107: 297-302.
Radic B, Fuchs R, Peraica M, Lucic A (1997) Ochratoxin A in human sera in the area with endemic nephropathy in Croatia. Toxicol Lett 91: 105-109.
Studer-Rohr I, Schlatter J, Dietrich DR (2000) Kinetic parameters and intraindividualfluctuatio ns of ochratoxin A plasma levels in humans. Arch Toxicol 74: 499-510.
Palli D, Miraglia M, Saieva C, et al. (1999) Serum levels of ochratoxin A in healthy adults in Tuscany: correlation with individualcharacteri stics and between repeat measurements. Cancer Epidemiol Biomarkers Prev 8: 265-269.
fraåk HK (1991) Food contamination by ochratoxin A in Germany. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H, eds. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumours. Lyon: IARC Scientific Publication No. 115. New York: Oxford University Press, pp. 77-81.
Skaug MA (1999) Analysis of Norwegian milk and infant formulas for ochratoxin A. Food Addit Contam 16: 75-78.
Davies TW, Palmer CR, Ruja E, Lipscombe JM (1996) Adolescent milk, dairy product and fruit consumption and testicular cancer. Br J Cancer 94: 657-660.
Sigurdson AJ, Chang S, Annegers JF, et al. (1999) A case-control study of diet and testicular carcinoma. Nutr Cancer 34: 20-26.
McMasters DR, Vedani A (1998) Ochratoxins: molecular strategies for developing an antidote. Altex 15: 218-221.
Obrecht-Pfumio S, Gross Y, Pfohl-Leszkowicz A, Dirheimer G (1996) Protection by indomethacin and aspirin against genotoxicity of ochratoxin A, particularly in the urinary bladder and kidney. Arch Toxicol 70: 244-248.
Gross Y, Chekir-Ghedira L, Huc A, et al. (1997) Retinol, ascorbic acid and a-tocopherolprevent DNA adduct formation in mice treated with the mycotoxins ochratoxin A and zearalenone. Cancer Lett 114: 225-229.
Creppy EE, Baudrimont I, Betbeder AM (1995) Prevention of nephrotoxicity of ochratoxin A, a food contaminant. Toxicol Lett 82-83: 869-877.
McNulty H, Cuskelly GJ, Ward M (2000) Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neuraltube defects. Am J Clin Nutr 71 (Suppl. 5): 1308S-1311S.
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Schwartz, G.G. Hypothesis: Does ochratoxin A cause testicular cancer?. Cancer Causes Control 13, 91–100 (2002). https://doi.org/10.1023/A:1013973715289
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DOI: https://doi.org/10.1023/A:1013973715289