Environment and Male Reproductive Function

  • N. Jørgensen
  • J. Toppari
  • P. Grandjean
  • N. E. Skakkebæk
Part of the Mineralogical Society Series book series (ENDO, volume 5)


Environmental impact on male reproductive function has gained increased attention because of adverse trends in male reproductive health. In some geographical areas, the incidence of testicular cancer has increased up to 3-fold, while mean sperm counts in healthy men appear to have declined by up to 50%. Further, the rate of congenital malformations of the male reproductive system has increased. Environmental rather than genetic factors must be invoked as explanation for the observed changes, because these have appeared within 1–2 generations, although genetic susceptibility could well confer an increased sensitivity to certain exogenous exposures.


Germ Cell Sertoli Cell Leydig Cell Testicular Cancer Sperm Count 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adami H, Bergström R, Möhner M, Zatonski W, Storm H, Ekbom A, Tretli S, Teppo L, Ziegler H, Rahu M, Gurevicius R, and Stengrevics A. Testicular cancer in nine Northern European countries. Int J Cancer 1994; 59: 33–38.PubMedCrossRefGoogle Scholar
  2. Allan BB, Brant R, Seiden JE, and Jarrell JF. Declining sex ratios in Canada. Can Med Assoc J 1997; 156: 37–40.Google Scholar
  3. Ansell PE, Bennett V, Bull D, Jackson MB, Pike LA, M. Pike C, Chilvers CED, Dudley NE, Gough MH, Griffiths DM, Redman C, Wilkinson AR, Macfarlane A, and Coupland CAC. Cryptorchidism: a prospective study of 7500 consecutive male births, 1984-8. Arch Dis Child 1992; 67: 892–899.Google Scholar
  4. Auger J, Kunstmann JM, Czyglik F, and Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med 1995; 332: 281–285.PubMedCrossRefGoogle Scholar
  5. Bergman A, Brandt I, Brouwer B, Harrison P, Holmes P, Keiding N, Randall G, Sharpe R, and Skakkebæk NE. European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife. ed. A. Bergman. Anonymous Weybridge, United Kingdom, 1–125, 1996.Google Scholar
  6. Berthelsen JG, Skakkebæk NE, von der Maase H, Sciensen BL, and Mogensen P. Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. Br Med J 1982; 285:1683–1686.Google Scholar
  7. Bjcrge C, Wiger R, Holme JA, Brunborg G, Andersen R, Dybing E, and Scderlund EJ. In vitro toxicity of 1,2-dibromo-3-chloropropane (DBCP) in different testicular cell types from rats. Reprod Toxicol 1995; 9: 461–473.CrossRefGoogle Scholar
  8. Bonde JP, and Giwercman A. Occupational hazards to male fecundity. Reprod Med Review 1995; 4: 59–73.Google Scholar
  9. Boyle P, Kaye SB, and Robertson AG. Changes in testicular cancer in Scotland. Eur J Cancer Clin Oncol 1987; 23: 827–830.PubMedCrossRefGoogle Scholar
  10. Bromen K, and Jöckei K. Change in male proportion among newborn infants. Lancet 1997; 349: 804–805, 1997.PubMedCrossRefGoogle Scholar
  11. Brown LM, Pottern LM, Hoover RN, Devesa SS, Aselton P, and Flannery JT. Testicular cancer in the Unites States: trends in incidence and mortality. Int J Epidemiol 1986; 15: 164–170.PubMedCrossRefGoogle Scholar
  12. Carlsen E, Giwercman A, Keiding N, and Skakkebæk NE. Evidence for decreasing quality of semen during past 50 years. BMJ 1992; 305:609–613.PubMedGoogle Scholar
  13. Cortes D, Müller J, and Skakkebæk NE. Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Int J Androl 1987; 10: 589–596.PubMedGoogle Scholar
  14. Damjanov I. Pathobiology of human germ cell neoplasia, Berlin: Springer-Verlag, pp. 1–19 1991.Google Scholar
  15. de Mouzon J, Thonneau P, Spira A, and Multigner L. Semen quality has declined among men born in France since 1950. BMJ 1996; 313:431.Google Scholar
  16. Dieckmann WJ, Davis ME, Rynkiewicz LM, and Pottinger RE. Does administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol 1953; 66: 1062.PubMedGoogle Scholar
  17. Feitosa MF, and Krieger H. Demography of the Human Sex Ratio in Some Latin American Countries, 1967-1986. Hum Biol 1992; 64:523–530.PubMedGoogle Scholar
  18. Fisch H, Goluboff ET, Olson JH, Feldshuh J, Broder SJ, and Barad DH. Semen analyses in 1,283 men from the United States over a 25-year period: no decline in quality. Fertil Steril 1996; 65: 1009–1014.PubMedGoogle Scholar
  19. Forman D, and Mcller H. Testicular cancer. Cancer Surv 1994; 19/20: 323–341.Google Scholar
  20. Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weiler PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN, Brook JD, and Schafer AJ. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 1994; 372: 525–530.PubMedCrossRefGoogle Scholar
  21. Gill WB, Schumacher GF, M. Bibbo M, F. H. Straus FH, and Schoenberg HW. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities J Urol 1979; 122: 36–39.Google Scholar
  22. Gill WB, Schumacher GFB, and Bibbo M. Genital and semen abnormalities in adults males two and one-half decades after in utero exposure to diethylstilbestrol. In: Intrauterine Exposure to Diethylstilbestrol in the Human, ed. A. L. Herbst. Chicago: American College of Obstetricians and Gynecologists, p. 53, 1978.Google Scholar
  23. Giwercman A, Bruun E, Frimodt-Mcller C, and Skakkebæk NE. Prevalence of carcinoma in situ and other histopathological abnormalities in testes of men with a history of cryptorchidism. J Urol 1989; 142: 998–1002.PubMedGoogle Scholar
  24. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Münsterberg A, Vivian N, Goodfellow P, and Lovell-Badge R. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 1990; 346: 245–250.PubMedCrossRefGoogle Scholar
  25. H. Mcller H. Change in male:female ratio among newborn infants in Denmark. Lancet 1996; 348: 828–829.Google Scholar
  26. Hakulinen T, Andersen A, Malker B, Pukkala E, Schou G, and Tulinius H. Trends in cancer incidence in the Nordic countries. APMIS 1986; 94: 7–166.Google Scholar
  27. Hass U, Jakobsen BM, Brandorff NP, Jelnes JE, and Petersen SH. Reproductive toxicants in the working environment (Reproduktionsskadende kemiske stoffer i arbejdsmiljcet), Copenhagen: Danish National Institute of Occupational Health, 1991.Google Scholar
  28. Hohlbein R. Missbildungsfrequenz in Dresden. Zentralblatt für Gynäkologie 1959; 18: 719–731.Google Scholar
  29. Ikeda Y, Shen W-H, Ingraham HA, and Parker KL. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol 1994; 8: 654–662.PubMedCrossRefGoogle Scholar
  30. Irvine S, Cawood E, Richardson D, MacDonald E, and Aitken J. Evidence of deteriorating semen quality in the United Kingdom: birth cohort study in 577 men in Scotland over 11 years. Br Med J 1996; 312: 467–471.Google Scholar
  31. Jcrgensen N, Rajpert-De Meyts E, Græm N, Müller J, Giwercman A, and Skakkebæk NE Expression of immunohistochemical markers for testicular carcinoma in situ by normal human fetal germ cells. Lab Invest 1995; 72: 223–231.Google Scholar
  32. James WH. Male reproductive hazards and occupation. Lancet 1996; 347: 773.PubMedCrossRefGoogle Scholar
  33. Jensen TK, Henriksen TB, Hjollund NH, Scheike T, Kolstad H, Giwercman A, Ernst E, Bonde JP, Skakkebæk NE, and Olsen J. Adult and prenatal exposure to tobacco smoke as risk indicators of fertility among 430 Danish couples. Am J Epidemiol. In press. Google Scholar
  34. Jirasek JE. Principles of reproductive embryology. In: Disorders of Sexual Differentiation, ed. J. L. Simpson. New York: Academic Press, pp. 51–110, 1976.Google Scholar
  35. Katzenellenbogen JA, O’Malley BW, and Katzenellenbogen BS. Tripartite steroid hormone receptor pharmalcology: interaction with multiple effector sites as a basis for the cell-and promoter-specific action of these hormones. Mol Endocrinol 1996; 10:119–131.PubMedCrossRefGoogle Scholar
  36. Kelce WR, and Wilson EM. Environmental antiandrogens:development effects, molecular mechanisms, and clinical implications. J Mol Med 1997; 75: 198–207.PubMedCrossRefGoogle Scholar
  37. Ku WW, Chapin RE, Wine RN, and Gladen BC. Testicular toxicity of boric acid: Relationship of dose to lesion development and recovery in the F344 rat. Reprod Toxicol 1993; 7: 305–319.PubMedCrossRefGoogle Scholar
  38. Leroith D, Potashnik G, Dunn J, and Spitz IM. The Exaggerated Prolactin Response to Thyrotropin-Releasing Hormone and Metoclopramide in 1,2-Dibromo-3-Chloropropane-Induced Azoospermia. J Clin Endocrinol Metab 1981; 52: 38–41.PubMedGoogle Scholar
  39. Mcller H. Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur Uro 1993; 23: 8–15.Google Scholar
  40. Manuel M, Katayama KP, and Jones HW, The age of occurence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol 1976; 124: 293–300.PubMedGoogle Scholar
  41. Matlai P, and Beral V. Trends in congenital malformations of external genitalia. Lancet 1985; i: 108.CrossRefGoogle Scholar
  42. Mattison DR and Thomford PJ. Selection of animals for reproductive toxicology studies: an evaluation of selected assumptions in reproductive toxicity testing and risk assessment. In: Human Risk Assessment-The Role of Animal Selection and Extrapolation, eds. M. V. Roloff, A. G. E. Wilson, W. E. Ribelin, W. P. Ridley, and F. A. Ruecker. New York: Taylor & Francis, 195–213, 1987.Google Scholar
  43. Miller GE, Welsh MJ, and Brabec MJ. Alteration of lactate metabolism in Sertoli cells and spermatocytes by 1,2-dibromo-3-chloropropane. Toxocologist 1985; 5: 1201.Google Scholar
  44. Mocarelli P, Brambilla P, Gerthoux PM, Patterson Jr DG, and Needham LL. Change in sex ratio with exposure to dioxin. Lancet 1996; 348: 409.PubMedCrossRefGoogle Scholar
  45. Müller J, Skakkebæk NE, Ritzén EM, Plöen L, and Petersen KE Carcinoma in situ of the testis in children with 45, X/46, XY gonadal dysgenesis. J Pediatr 1985;106: 431–436.PubMedCrossRefGoogle Scholar
  46. Müller J, and Skakkebæk NE. Testicular carcinoma in situ in children with androgen insensitivity (testicular feminisation) syndrome. Br Med J 1984; 288: 1419–1420.Google Scholar
  47. Müller J. Morphometry and histology of gonads from twelve children and adolescents with the androgen insensitivity (testicular feminization) syndrome. J Clin Endocrinol Metab 1984; 59: 785–789.PubMedGoogle Scholar
  48. Nüesch-Bachmann IH, and Hedinger C. Atypische Spermatogonien als Präkanzerose. Schweiz Med Wochenschr 1977; 107: 795–801.PubMedGoogle Scholar
  49. Olsen GW, Lanham JM, Bodner KM, Hylton DB, and Bond GG. Determinants of spermatogenesis recovery among workers exposed to 1,2-dibromo-3-chloropropane. J Occup Med 1990; 32: 979–984.PubMedCrossRefGoogle Scholar
  50. O’Malley BW, Schrader WT, Mani S, Smith C, Weigel NL, Conneely OM, and Clark JH. An alternative ligand-independent pathway for activation of steroid receptors. Recent Prog Horm Res 1995;50:333–347.PubMedGoogle Scholar
  51. Orth JM, Gunsalus GL, and Lamperti AA. Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 1988; 122: 787–794.PubMedGoogle Scholar
  52. Østerlind A. Diverging trends in incidence and mortality of testicular cancer in Denmark, 1943-1982. Br J Cancer 1986; 53: 501–505.PubMedGoogle Scholar
  53. Palmlund I, Apfel R, Buitendijk S, Cabau A, and Forsberg J-G. Effects of diethylstilbestrol (DES) medication during pregnancy: report from a symposium at the 10th International Congress of ISPOG. J Psychosom Obstet Gynaecol 1993; 14: 71–89.PubMedGoogle Scholar
  54. Paulozzi LJ, Erickson JD, and Jackson RJ. Hypospadias trends in two US surveillance systems. Pediatrics 1997; 100: 831–834.PubMedCrossRefGoogle Scholar
  55. Paulsen CA, Berman NG, and Wang C. Data from men in greater Seattle area reveals no downward trend in semen quality: futher evidence that deterioration of semen quality is not geographically uniform. Fertil Steril 1996; 65:1015–1020.PubMedGoogle Scholar
  56. Potashnik G, Ben-Aderet N, Israeli R, Yanai-Inbar I, and Sober I. Suppresive effect of 1,2-dibromo-3-chloropropane on human spermatogenesis. Fertil Steril 1978; 30: 444–447.PubMedGoogle Scholar
  57. Potashnik G, and Abeliovich D. Chromosomal Analysis and Health Status of Children Conceived to Men During or Following Dibromochloropropane-Induced Spermatogenic Suppression. Andrologia 1985; 17:291–296.PubMedGoogle Scholar
  58. Potashnik G, and Porath A. Dibromochloropropane (DBCP): A 17-year Reassessment of Testicular Function and Reproductive Performance. JOEM 1995; 37: 1287–1292.PubMedCrossRefGoogle Scholar
  59. Potashnik G, and Yanai-Inbar I. Dibromochloropropane (DBCP): An 8-year reevaluation of testicular function and reproductive performance. Fertil Steril 1987; 47: 317–323.PubMedGoogle Scholar
  60. Pryor JP, Cameron KM, Chilton CP, Ford TF, Parkinson MC, Sinokrot J, and Westwood CA. Carcinoma in situ in testicular biopsies from men presenting with infertility. Br J Urol 1983; 55: 780–784.PubMedGoogle Scholar
  61. Rajpert-De Meyts E, and Skakkebæk NE. The possible role of sex hormones in the development of testicular cancer Eur Urol 1993; 23: 54–61.Google Scholar
  62. Russell LD, and Peterson RN. Determination of the elongate spermatid-Sertoli cell ratio in various mammals. J Reprod Fertil 1984; 70: 635–641.PubMedGoogle Scholar
  63. Schecter A, McGee H, Stanley HS, Boggess K, and Brandt-Raud P. Dioxins and dioxin-like chemicals in blood and semen of American Vietnam veterans from the state of Michigan Am J Ind Med 1996; 30: 647–654.PubMedCrossRefGoogle Scholar
  64. Scorer CG. The descent of the testis. Arch Dis Child 1964; 39: 605–609.PubMedCrossRefGoogle Scholar
  65. Sharpe RM, Maguire SM, Saunders PT, Millar MR, Russel LD, Ganten D, Bachmann S, Mullins L, and Mullins JJ. Infertility in a transgenic rat due to impairment of cytoplasmic elimination and sperm release from the Sertoli cells. Biol Reprod 1995; 53: 214–226.CrossRefGoogle Scholar
  66. Shemi DZ, Marx J, Kaplanski J, Potashnik G, and Sod-Moriah UA. Testicular damage development in rats injected with dibromochloropropane (DBCP). Andrologia 1988; 20:331–337.PubMedGoogle Scholar
  67. Skakkebæk NE, Berthelsen JG, Giwercman A, and Müller J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 1987; 10: 19–28.PubMedGoogle Scholar
  68. Skakkebæk NE, Rajpert-De Meyts E, Jcrgensen N, Carlsen E, Petersen PM, Giwercman A, Andersen A-G, Jensen TK, Andersson A-M, and Müller J. Germ cell cancer and disorders of spermatogenesis: an environmental connection? APMIS 1998; 106: 3–12.PubMedCrossRefGoogle Scholar
  69. Skakkebæk NE. Carcinoma in situ of the testis: frequency and relationship to invasive germ cell tumours in infertile men. Histopathology 1978; 2: 157–170.PubMedCrossRefGoogle Scholar
  70. Sod-Moriah UA, Shemi D, Potashnik G, and Kaplanski J. Age-dependent differences in the effects of 1,2-dibromo-3-chloropropane (DBCP) on fertility, sperm count, testicular histology and hormonal profile in rats. Andrologia 1990; 22: 455–462.PubMedGoogle Scholar
  71. Stenchever MA, Williamson RA, Leonard J, Karp LE, Ley B, Shy K, and Smith D. Possible relationship between in utero diethylstilbetrol exposure and male fertility. Am J Obstet Gynecol 1981; 140: 186–193.PubMedGoogle Scholar
  72. Stillman RJ. In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance in male and female offspring. Am J Obstet Gynecol 1982; 142: 905–921.PubMedGoogle Scholar
  73. Swan SH, Elkin EP, and Fenster L. Have Sperm Densities Declined? A Reanalysis of Global Trend Data. Environ Health Perspect 1997;105: 1228–1232.PubMedCrossRefGoogle Scholar
  74. Sweet RA, H. Schrott HG, Kurland R, and Culp OS. Study of the incidence of hypospadias in Rochester, Minnesota, 1940-1970, and a case-contol comparison of possible etiologic factors. Mayo Clin Proc 1974; 49: 52–58.PubMedGoogle Scholar
  75. Tas S, Lauwerys R, and Lison D. Occupational Hazards for the Male Reproductive System. Critical Rev Toxicol 1996; 26:261–307.Google Scholar
  76. Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJJ, Jégou B, Jensen TK, Jouannet P, Keiding N, Leffers H, McLachlan JA, Meyer O, Müller J, Rajpert-De Meyts E, Scheike T, Sharpe R, Sumpter J, and Skakkebæk NE. Male reproductive health and environmental xenoestrogens Environ Health Perspect 1996; 104: 741–803.Google Scholar
  77. Torkelson TR, Sadek SE, and Rowe VK. Toxicologic Investigations of 1, 2-Dibromo-3-Chloropropane. Toxicol Appl Pharmacol 1961; 3: 545–559.PubMedCrossRefGoogle Scholar
  78. van der Pal-de Bruin K, Verloove-Vanhorick SP, and Roeleveld N. Change in male-female ratio among newborn babies in Netherlands. Lancet 1997; 349:62.PubMedGoogle Scholar
  79. Vierula M, Niemi M, Keiski A, Saaranen M, Saarikoski S, and Suominen J. High and unchanged sperm counts of Finnish men. Int J Androl 1996; 19: 11–17.PubMedGoogle Scholar
  80. vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, and Welshons WV. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci USA 1997; 94:2056–2061.CrossRefGoogle Scholar
  81. von der Maase H, M. R¢rth M, S. Walbom-J¢rgensen S, B. L. S¢rensen BL, I. S. Christophersen IS, Hald T., Jacobsen GK., J. G. Berthelsen JG, and N. E. Skakkebæk NE. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Br Med J 1986; 293: 1398–1401, 1986.Google Scholar
  82. WHO. Congenital Malformations Worldwide: A Report from The International Clearinghouse for Birth Defects Monitoring Systems, Oxford: Elsevier, 1991; 113–118.Google Scholar
  83. Whorton D, Krauss RM, Marshall R, and Milby TH. Infertility in male pesticide workers. Lancet 1977; ii: 1259–1261.CrossRefGoogle Scholar
  84. Whorton MD, and Milby TH. Recovery of Testicular Function Among DBCP Workers. J Occup Med 1980; 22:177–179.PubMedGoogle Scholar
  85. Wilcox AJ, Baird DD, Weinberg CR, Hornsby PP, and Herbst AL. Fertility in men exposed prenatally to diethylstilbestrol. N Engl J Med1995; 332: 1411–1416.PubMedCrossRefGoogle Scholar
  86. Wilson JD, and Lasnitzki I. Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology, 1971; 89: 659–668.PubMedCrossRefGoogle Scholar
  87. Wilson JD, George FW, and Renfree MB. The endocrine role in mammalian sexual differentiation. Recent Prog Horm Res 1995; 50: 349–364.PubMedGoogle Scholar
  88. Witschi E. Migration of the germ cells of human embryos from the yolk sac to the primitive gonadal folds. In: Contributions to Embryology. No. 209, Anonymous Washington D.C. Carnegie Institute of Washington, pp. 69–80 1948.Google Scholar
  89. Xu B, Chia SE, Tsakok M, and Ong CN. Trace elements in blood and seminal plasma and their relationship to sperm quality Reprod Toxicol 1993; 7: 613–618.Google Scholar

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© Kluwer Academic Publishers 1999

Authors and Affiliations

  • N. Jørgensen
    • 1
  • J. Toppari
    • 1
  • P. Grandjean
    • 1
  • N. E. Skakkebæk
    • 1
  1. 1.National University HospitalCopenhagenDenmark

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