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Environmental factors in declining human fertility

Nature Reviews Endocrinology volume 18, pages 139–157 (2022)Cite this article

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Abstract

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.

Key points

  • Industrialized regions have birth rates so low that their populations cannot be sustained; declines in birth rates are generally ascribed to socioeconomic and cultural factors, although human infertility is widespread.

  • Decreasing fertility rates were already recorded around 1900 in Denmark, a few decades after the beginning of utilization of fossil fuels that were, and still are, drivers of modern industrialization and wealth.

  • We hypothesize that declines in fertility rates might be linked to exposures to chemicals originating from fossil fuels causing human reproductive problems and cancer; early gestation might be a sensitive period.

  • The current unsustainable birth rates will eventually result in decreasing populations.

  • A key research challenge remains: how to distinguish biological from socioeconomic and behavioural factors?

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Fig. 1: Total fertility rates in the European Union, Japan and the USA, 1960–2018.
Fig. 2: Total fertility rate, Denmark, 1901–2019.
Fig. 3: Changes in average sperm concentrations 1973–2011.
Fig. 4: Testicular cancer incidence trends in selected countries/regions worldwide.
Fig. 5: Illustration of epigenetic drift.
Fig. 6: Adverse outcome pathway network for the induction of male reproductive malformations.
Fig. 7: Expression of the embryonic marker OCT4 in adult germ cell neoplasia in situ is similar to expression in germ cells (gonocytes) in normal fetal gonads.
Fig. 8: Testicular dysgenesis syndrome.
Fig. 9: Levels of unsustainable fertility rates and population sizes (newborn babies) over three generations.

References

  1. Vollset, S. E. et al. Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the Global Burden of Disease Study. Lancet 396, 1285–1306 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lee, S. J., Li, L. & Hwang, J. Y. After 20 years of low fertility, where are the obstetrician-gynecologists? Obstet. Gynecol. Sci. 64, 407–418 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lutz, W., O’Neill, B. C. & Scherbov, S. Demographics. Europe’s population at a turning point. Science 299, 1991–1992 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. GBD 2017 Population and Fertility Collaborators. Population and fertility by age and sex for 195 countries and territories, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1995–2051 (2018).

    Article  Google Scholar 

  5. Zegers-Hochschild, F. et al. The international glossary on infertility and fertility care, 2017. Hum. Reprod. 32, 1786–1801 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Priskorn, L., Dahl, C. L., Pihl, A. S., Skakkebaek, N. E. & Juul, A. High maternal age at first and subsequent child births in Denmark in the mid-1800s–Letter to the editor. Eur. J. Obstet. Gynecol. Reprod. Biol. 241, 137–138 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Fellman, J. & Eriksson, A. W. Temporal differences in the regional twinning rates in Sweden after 1750. Twin Res. 6, 183–191 (2003).

    Article  PubMed  Google Scholar 

  8. Blomberg, J. M., Priskorn, L., Jensen, T. K., Juul, A. & Skakkebaek, N. E. Temporal trends in fertility rates: a vationwide registry based study from 1901 to 2014. PloS ONE 10, e0143722 (2015).

    Article  Google Scholar 

  9. Lackie, E. & Fairchild, A. The birth control pill, thromboembolic disease, science and the media: a historical review of the relationship. Contraception 94, 295–302 (2016).

    Article  PubMed  Google Scholar 

  10. Sandström, G., Marklund, E. Fertility differentials in Sweden during the first half of the twentieth century: the changing effect of female labor force participation and occupational field. Presented at the Annual Meeting of the Population Association of America, Chicago, 27–29 April 2017.

  11. Skakkebaek, N. E. et al. Populations, decreasing fertility, and reproductive health. Lancet 393, 1500–1501 (2019).

    Article  PubMed  Google Scholar 

  12. Oeppen, J. & Vaupel, J. W. Demography. Broken limits to life expectancy. Science 296, 1029–1031 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Statistics Bureau of Japan. Japan’s Population Estimates Released https://www.stat.go.jp/english/info/news/1910.html (2010).

  14. Tillotson, J. E. America’s obesity: conflicting public policies, industrial economic development, and unintended human consequences. Annu. Rev. Nutr. 24, 617–643 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Haagen-Smit, A. J. A lesson from the smog capital of the world. Proc. Natl Acad. Sci. USA 67, 887–897 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang, F., Zheng, P., Dai, J., Wang, H. & Wang, R. Fault tree analysis of the causes of urban smog events associated with vehicle exhaust emissions: a case study in Jinan, China. Sci. Total. Environ. 668, 245–253 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. World Health Organization. State of the Science of Endocrine Disputing Chemicals – 2012. https://www.unep.org/resources/publication/state-science-endocrine-disputing-chemicals-ipcp-2012 (2013).

  18. Crinnion, W. J. The CDC fourth national report on human exposure to environmental chemicals: what it tells us about our toxic burden and how it assist environmental medicine physicians. Altern. Med. Rev. 15, 101–109 (2010).

    PubMed  Google Scholar 

  19. Bergman, A. et al. The impact of endocrine disruption: a consensus statement on the state of the science. Environ. Health Perspect. 121, A104–A106 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Andersson, A. M. et al. Adverse trends in male reproductive health: we may have reached a crucial ‘tipping point’. Int. J. Androl. 31, 74–80 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Christin-Maitre, S. History of oral contraceptive drugs and their use worldwide. Best. Pract. Res. Clin. Endocrinol. Metab. 27, 3–12 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Mears, E. Clinical trials of oral contraceptives. Br. Med. J. 2, 1179–1183 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Finer, L. B. & Zolna, M. R. Declines in unintended pregnancy in the United States, 2008-2011. N. Engl. J. Med. 374, 843–852 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mumford, S. L., Sapra, K. J., King, R. B., Louis, J. F. & Buck Louis, G. M. Pregnancy intentions–a complex construct and call for new measures. Fertil. Steril. 106, 1453–1462 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sedgh, G. et al. Abortion incidence between 1990 and 2014: global, regional, and subregional levels and trends. Lancet 388, 258–267 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jatlaoui, T. C. et al. Abortion surveillance – United States, 2016. MMWR Surveill. Summ. 68, 1–41 (2019).

    Article  PubMed  Google Scholar 

  27. Jensen, T. K. et al. Declining trends in conception rates in recent birth cohorts of native Danish women: a possible role of deteriorating male reproductive health. Int. J. Androl. 31, 81–92 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lassen, T. H. et al. Trends in rates of natural conceptions among Danish women born during 1960-1984. Hum. Reprod. 27, 2815–2822 (2012).

    Article  PubMed  Google Scholar 

  29. Hognert, H. et al. High birth rates despite easy access to contraception and abortion: a cross-sectional study. Acta Obstet. Gynecol. Scand. 96, 1414–1422 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Lidegaard, Ø. et al. Pregnancy loss: A 40-year nationwide assessment. Acta Obstet. Gynecol. Scand. 99, 1492–1496 (2020).

    Article  PubMed  Google Scholar 

  31. Rossen, L. M., Ahrens, K. A. & Branum, A. M. Trends in risk of pregnancy loss among US women, 1990-2011. Paediatr. Perinat. Epidemiol. 32, 19–29 (2018).

    Article  PubMed  Google Scholar 

  32. Tong, S. & Short, R. V. Dizygotic twinning as a measure of human fertility. Hum. Reprod. 13, 95–98 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Asklund, C. et al. Twin pregnancy possibly associated with high semen quality. Hum. Reprod. 22, 751–755 (2007).

    Article  PubMed  Google Scholar 

  34. Pison, G., Monden, C. & Smits, J. Twinning rates in developed countries: trends and explanations. Popul. Dev. Rev. 41, 629–649 (2015).

    Article  Google Scholar 

  35. Präg, P. & Mills, M. C. in Childlessness in Europe: Contexts, Causes, and Consequences (eds Kreyenfeld, M. & Konietzka, D.) 289–309 (Springer, 2017).

  36. Bracken, M. B. Oral contraception and twinning: an epidemiologic study. Am. J. Obstet. Gynecol. 133, 432–434 (1979).

    Article  CAS  PubMed  Google Scholar 

  37. Rachootin, P. & Olsen, J. Secular changes in the twinning rate in Denmark 1931 to 1977. Scand. J. Soc. Med. 8, 89–94 (1980).

    Article  CAS  PubMed  Google Scholar 

  38. Olsen, J. & Rachootin, P. The end of the decline in twinning rates? Scand. J. Soc. Med. 11, 119 (1983).

    CAS  PubMed  Google Scholar 

  39. Andersen, A. N. & Erb, K. Register data on assisted reproductive technology (ART) in Europe including a detailed description of ART in Denmark. Int. J. Androl. 29, 12–16 (2006).

    Article  Google Scholar 

  40. De Geyter, C. et al. ART in Europe, 2015: results generated from European registries by ESHRE. Hum. Reprod. Open 2020, hoz038 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kamphuis, E. I., Bhattacharya, S., van der Veen, F., Mol, B. W. & Templeton, A. Are we overusing IVF? BMJ 348, g252 (2014).

    Article  PubMed  Google Scholar 

  42. Sundhedsdatastyrelsen. Assisteret Reproduktion 2019. https://docplayer.dk/204335156-Assisteret-reproduktion-2019.html (2019).

  43. Garcia, D., Brazal, S., Rodriguez, A., Prat, A. & Vassena, R. Knowledge of age-related fertility decline in women: a systematic review. Eur. J. Obstet. Gynecol. Reprod. Biol. 230, 109–118 (2018).

    Article  PubMed  Google Scholar 

  44. Habbema, J. D., Eijkemans, M. J., Leridon, H. & te Velde, E. R. Realizing a desired family size: when should couples start? Hum. Reprod. 30, 2215–2221 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hassan, M. A. & Killick, S. R. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil. Steril. 79 (Suppl 3), 1520–1527 (2003).

    Article  PubMed  Google Scholar 

  46. Tsao, C. W. et al. Exploration of the association between obesity and semen quality in a 7630 male population. PLoS ONE 10, e0119458 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Nieschlag, E., Lammers, U., Freischem, C. W., Langer, K. & Wickings, E. J. Reproductive functions in young fathers and grandfathers. J. Clin. Endocrinol. Metab. 55, 676–681 (1982).

    Article  CAS  PubMed  Google Scholar 

  48. Ge, Z. J., Schatten, H., Zhang, C. L. & Sun, Q. Y. Oocyte ageing and epigenetics. Reproduction 149, R103–R114 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gruhn, J. R. et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466–1469 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Handyside, A. H. Molecular origin of female meiotic aneuploidies. Biochim. Biophys. Acta 1822, 1913–1920 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Newman, J. E., Fitzgerlad, O., Paul, R. C. & Chambers, G. M. Assisted reproductive technology in Australia and New Zealand 2017. https://npesu.unsw.edu.au/sites/default/files/npesu/data_collection/Assisted%20Reproductive%20Technology%20in%20Australia%20and%20New%20Zealand%202017.pdf (2019).

  52. Neels, K., Murphy, M., Ni Bhrolchain, M. & Beaujouan, E. Rising educational participation and the trend to later childbearing. Popul. Dev. Rev. 43, 667–693 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Joham, A. E., Palomba, S. & Hart, R. Polycystic ovary syndrome, obesity, and pregnancy. Semin. Reprod. Med. 34, 93–101 (2016).

    Article  PubMed  Google Scholar 

  54. Koninckx, P. R. et al. The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear. Best. Pract. Res. Clin. Obstet. Gynaecol. 71, 14–26 (2021).

    Article  PubMed  Google Scholar 

  55. Noriega, N. C., Ostby, J., Lambright, C., Wilson, V. S. & Gray, L. E. Jr. Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male but not female rat offspring. Biol. Reprod. 72, 1324–1335 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Buck Louis, G. M. et al. Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE study. Andrology 4, 639–647 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. Lum, K. J., Sundaram, R., Barr, D. B., Louis, T. A. & Buck Louis, G. M. Perfluoroalkyl chemicals, menstrual cycle length, and fecundity: findings from a prospective pregnancy study. Epidemiology 28, 90–98 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mínguez-Alarcón, L. & Gaskins, A. J. Female exposure to endocrine disrupting chemicals and fecundity: a review. Curr. Opin. Obstet. Gynecol. 29, 202–211 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Buck Louis, G. M., Kannan, K., Sapra, K. J., Maisog, J. & Sundaram, R. Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples’ fecundity. Am. J. Epidemiol. 180, 1168–1175 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Smarr, M. M., Sundaram, R., Honda, M., Kannan, K. & Louis, G. M. Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples’ fecundity. Environ. Health Perspect. 125, 730–736 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Abu-Halima, M. et al. Panel of five microRNAs as potential biomarkers for the diagnosis and assessment of male infertility. Fertil. Steril. 102, 989–997 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Steinmetz, R., Brown, N. G., Allen, D. L., Bigsby, R. M. & Ben-Jonathan, N. The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology 138, 1780–1786 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Steinmetz, R. et al. The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract. Endocrinology 139, 2741–2747 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Spearow, J. L., Doemeny, P., Sera, R., Leffler, R. & Barkley, M. Genetic variation in susceptibility to endocrine disruption by estrogen in mice. Science 285, 1259–1261 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Spearow, J. L. et al. Genetic variation in physiological sensitivity to estrogen in mice. APMIS 109, 356–364 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Spearow, J. L. & Barkley, M. Reassessment of models used to test xenobiotics for oestrogenic potency is overdue. Hum. Reprod. 16, 1027–1029 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Amann, R. P. & Howards, S. S. Daily spermatozoal production and epididymal spermatozoal reserves of the human male. J. Urol. 124, 211–215 (1980).

    Article  CAS  PubMed  Google Scholar 

  68. Franca, L. R., Russell, L. D. & Cummins, J. M. Is human spermatogenesis uniquely poor? Ann. Rev. Biomed. Sci. 4, 19–40 (2002).

    Google Scholar 

  69. Short, R. V. The testis: the witness of the mating system, the site of mutation and the engine of desire. Acta Paediatr. Suppl. 422, 3–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Hess, R. A. & França, L. R. in Molecular Mechanisms in Spermatogenesis (ed. Cheng, C.) 1–15 (Landes Bioscience, 2007).

  71. França, L. R., Ogawa, T., Avarbock, M. R., Brinster, R. L. & Russell, L. D. Germ cell genotype controls cell cycle during spermatogenesis in the rat. Biol. Reprod. 59, 1371–1377 (1998).

    Article  PubMed  Google Scholar 

  72. França, L. R., Avelar, G. F. & Almeida, F. F. Spermatogenesis and sperm transit through the epididymis in mammals with emphasis on pigs. Theriogenology 63, 300–318 (2005).

    Article  PubMed  Google Scholar 

  73. Carlsen, E., Giwercman, A., Keiding, N. & Skakkebæk, N. E. Evidence for decreasing quality of semen during past 50 years. BMJ 305, 609–613 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Levine, H. et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum. Reprod. Update 23, 646–659 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Huang, C. et al. Decline in semen quality among 30,636 young Chinese men from 2001 to 2015. Fertil. Steril. 107, 83–88.e2 (2017).

    Article  PubMed  Google Scholar 

  76. Yuan, H. F. et al. Decline in semen concentration of healthy Chinese adults: evidence from 9357 participants from 2010 to 2015. Asian J. Androl. 20, 379–384 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Huang, X. et al. Association of exposure to ambient fine particulate matter constituents with semen quality among men attending a fertility center in China. Environ. Sci. Technol. 53, 5957–5965 (2019).

    Article  CAS  PubMed  Google Scholar 

  78. Priskorn, L. et al. Average sperm count remains unchanged despite reduction in maternal smoking: results from a large cross-sectional study with annual investigations over 21 years. Hum. Reprod. 33, 998–1008 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Jørgensen, N. et al. Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men. BMJ Open 2, e000990 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Bonde, J. P. E. et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 352, 1172–1177 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Guzick, D. S. et al. Sperm morphology, motility, and concentration in fertile and infertile men. N. Engl. J. Med. 345, 1388–1393 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Slama, R. et al. Time to pregnancy and semen parameters: a cross-sectional study among fertile couples from four European cities. Hum. Reprod. 17, 503–515 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. https://www.who.int/publications/i/item/9789240030787 (2021).

  84. Skakkebaek, N. E. Normal reference ranges for semen quality and their relations to fecundity. Asian J. Androl. 12, 95–98 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Skakkebæk, N. E., Rajpert-De Meyts, E. & Main, K. M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod. 16, 972–978 (2001).

    Article  PubMed  Google Scholar 

  86. Clemmesen, J. A doubling of morbidity from testis carcinoma in Copenhagen, 1943–1962. APMIS 72, 348–349 (1968).

    CAS  Google Scholar 

  87. Znaor, A. et al. Testicular cancer incidence predictions in Europe 2010-2035: a rising burden despite population ageing. Int. J. Cancer 147, 820–828 (2020).

    Article  CAS  PubMed  Google Scholar 

  88. Møller, H. Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur. Urol. 23, 8–15 (1993).

    Article  PubMed  Google Scholar 

  89. Bergström, R. et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J. Natl Cancer Inst. 88, 727–733 (1996).

    Article  PubMed  Google Scholar 

  90. Grumet, R. F. & MacMahon, B. Trends in mortality from neoplasms of the testis. Cancer 11, 790–797 (1958).

    Article  CAS  PubMed  Google Scholar 

  91. Case, R. A. Cohort analysis of cancer mortality in England and Wales; 1911–1954 by site and sex. Br. J. Prev. Soc. Med. 10, 172–199 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Article  PubMed  Google Scholar 

  93. Bray, F. et al. Cancer incidence in five continents, Vol. XI (electronic version). Lyon: International Agency for Research on Cancer. https://ci5.iarc.fr/CI5-XI/Default.aspx (2017).

  94. International Agency for Research on Cancer. CI5plus: Cancer Incidence in Five Continents Time Trends. http://ci5.iarc.fr/CI5plus/Default.aspx (2018).

  95. Znaor, A., Lortet-Tieulent, J., Jemal, A. & Bray, F. International variations and trends in testicular cancer incidence and mortality. Eur. Urol. 65, 1095–1106 (2014).

    Article  PubMed  Google Scholar 

  96. Harbuz, R. et al. A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation. Am. J. Hum. Genet. 88, 351–361 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dam, A. H. et al. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am. J. Hum. Genet. 81, 813–820 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tüttelmann, F., Ruckert, C. & Röpke, A. Disorders of spermatogenesis: perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med. Genet. 30, 12–20 (2018).

    PubMed  PubMed Central  Google Scholar 

  99. Krausz, C. & Riera-Escamilla, A. Genetics of male infertility. Nat. Rev. Urol. 15, 369–384 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Nagirnaja, L. et al. Variant PNLDC1, defective piRNA processing, and azoospermia. N. Engl. J. Med. 385, 707–719 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Kasak, L. & Laan, M. Monogenic causes of non-obstructive azoospermia: challenges, established knowledge, limitations and perspectives. Hum. Genet. 140, 135–154 (2020).

    Article  PubMed  Google Scholar 

  102. Barban, N. et al. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nat. Genet. 48, 1462–1472 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Stolk, L. et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat. Genet. 41, 645–647 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Day, F. R. et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat. Genet. 49, 834–841 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ruth, K. S. et al. Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan. Hum. Mol. Genet. 28, 1392–1401 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stolk, L. et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat. Genet. 44, 260–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lutzmann, M. et al. MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol. Cell 47, 523–534 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Cavalli, G. & Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 571, 489–499 (2019).

    Article  CAS  PubMed  Google Scholar 

  109. Almstrup, K. et al. Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood. Sci. Rep. 6, 28657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chen, S. et al. Age at onset of different pubertal signs in boys and girls and differential DNA methylation at age 10 and 18 years: an epigenome-wide follow-up study. Hum. Reprod. Open 2020, hoaa006 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Kresovich, J. K. et al. Reproduction, DNA methylation and biological age. Hum. Reprod. 34, 1965–1973 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Meehan, R. R., Thomson, J. P., Lentini, A., Nestor, C. E. & Pennings, S. DNA methylation as a genomic marker of exposure to chemical and environmental agents. Curr. Opin. Chem. Biol. 45, 48–56 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Almstrup, K., Frederiksen, H., Andersson, A. M. & Juul, A. Levels of endocrine-disrupting chemicals are associated with changes in the peri-pubertal epigenome. Endocr. Connect. 9, 845–857 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tobi, E. W. et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat. Commun. 5, 5592 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Richmond, R. C. et al. Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Hum. Mol. Genet. 24, 2201–2217 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Leitão, E. et al. The sperm epigenome does not display recurrent epimutations in patients with severely impaired spermatogenesis. Clin. Epigenet. 12, 61 (2020).

    Article  Google Scholar 

  117. Soubry, A. et al. Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm. Environ. Epigenet. 3, dvx003 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Wu, H. et al. Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study. Hum. Reprod. 32, 2159–2169 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Greeson, K. W. et al. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci. Rep. 10, 8567 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Beck, D., Sadler-Riggleman, I. & Skinner, M. K. Generational comparisons (F1 versus F3) of vinclozolin induced epigenetic transgenerational inheritance of sperm differential DNA methylation regions (epimutations) using MeDIP-Seq. Environ. Epigenet 3, dvx016 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Nätt, D. & Öst, A. Male reproductive health and intergenerational metabolic responses from a small RNA perspective. J. Intern. Med. 288, 305–320 (2020).

    Article  PubMed  Google Scholar 

  122. Trigg, N. A., Eamens, A. L. & Nixon, B. The contribution of epididymosomes to the sperm small RNA profile. Reproduction 157, R209–R223 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Xu, H. et al. MicroRNA expression profile analysis in sperm reveals hsa-mir-191 as an auspicious omen of in vitro fertilization. BMC Genomics 21, 165 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Nybo Andersen, A. M. & Urhoj, S. K. Is advanced paternal age a health risk for the offspring? Fertil. Steril. 107, 312–318 (2017).

    Article  PubMed  Google Scholar 

  128. Whorton, D., Milby, T. H., Krauss, R. M. & Stubbs, H. A. Testicular function in DBCP exposed pesticide workers. J. Occup. Med. 21, 161–166 (1979).

    CAS  PubMed  Google Scholar 

  129. Goldsmith, J. R., Potashnik, G. & Israeli, R. Reproductive outcomes in families of DBCP-exposed men. Arch. Environ. Health 39, 85–89 (1984).

    Article  CAS  PubMed  Google Scholar 

  130. Potashnik, G., Goldsmith, J. & Insler, V. Dibromochloropropane-induced reduction of the sex-ratio in man. Andrologia 16, 213–218 (1984).

    Article  CAS  PubMed  Google Scholar 

  131. Skakkebaek, N. E. et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol. Rev. 96, 55–97 (2016).

    Article  CAS  PubMed  Google Scholar 

  132. Messiaen, S. et al. Rad54 is required for the normal development of male and female germ cells and contributes to the maintainance of their genome integrity after genotoxic stress. Cell Death Dis. 4, e774 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mandl, A. M., Beaumont, H. M. & Hughes, G. C. in Effects of Ionizing Radiation on the Reproductive System (eds Carlson, W. D. & Gassner, F. X.) 165 (Pergamon Press, 1964).

  134. Mandl, A. M. The radiosensitivity of germ cells. Biol. Rev. 39, 288–371 (1964).

    Article  CAS  PubMed  Google Scholar 

  135. Gray, L. E. Jr. et al. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol. Sci. 58, 350–365 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Fisher, J. S., Macpherson, S., Marchetti, N. & Sharpe, R. M. Human “testicular dysgenesis syndrome”: a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum. Reprod. 18, 1383–1394 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Gray, L. E. Jr., Ostby, J. S. & Kelce, W. R. Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. Toxixol. Appl. Pharmacol. 129, 46–52 (1994).

    Article  CAS  Google Scholar 

  138. Hass, U. et al. Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ. Health Perspect. 115 (Suppl 1), 122–128 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Welsh, M. et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J. Clin. Invest. 118, 1479–1490 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Van den Driesche, S. et al. Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. JCI Insight 2, e91204 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Kortenkamp, A. Which chemicals should be grouped together for mixture risk assessments of male reproductive disorders? Mol. Cell Endocrinol. 499, 110581 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Howdeshell, K. L., Hotchkiss, A. K. & Gray, L. E. Jr Cumulative effects of antiandrogenic chemical mixtures and their relevance to human health risk assessment. Int. J. Hyg. Environ. Health 220, 179–188 (2017).

    Article  CAS  PubMed  Google Scholar 

  143. Gray, L. E. Jr & Ostby, J. S. In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive morphology and function in female rat offspring. Toxixol. Appl. Pharmacol. 133, 285–294 (1995).

    Article  CAS  Google Scholar 

  144. Lovekamp-Swan, T. & Davis, B. J. Mechanisms of phthalate ester toxicity in the female reproductive system. Environ. Health Perspect. 111, 139–145 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Guerra, M. T., Scarano, W. R., de Toledo, F. C., Franci, J. A. & Kempinas Wde, G. Reproductive development and function of female rats exposed to di-eta-butyl-phthalate (DBP) in utero and during lactation. Reprod. Toxicol. 29, 99–105 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Johansson, H. K. L. et al. Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals. Arch. Toxicol. 94, 3359–3379 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mocarelli, P. et al. Perinatal exposure to low doses of dioxin can permanently impair human semen quality. Environ. Health Perspect. 119, 713–718 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hardell, L., van Bavel, B., Lindstrom, G., Eriksson, M. & Carlberg, M. In utero exposure to persistent organic pollutants in relation to testicular cancer risk. Int. J. Androl. 29, 228–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  149. Krysiak-Baltyn, K. et al. Association between chemical pattern in breast milk and congenital cryptorchidism: modelling of complex human exposures. Int. J. Androl. 35, 294–302 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Main, K. M. et al. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ. Health Perspect. 115, 1519–1526 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hemminki, K. & Li, X. Cancer risks in Nordic immigrants and their offspring in Sweden. Eur. J. Cancer 38, 2428–2434 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Schmiedel, S., Schuz, J., Skakkebæk, N. E. & Johansen, C. Testicular germ cell cancer incidence in an immigration perspective, Denmark, 1978 to 2003. J. Urol. 183, 1378–1382 (2010).

    Article  PubMed  Google Scholar 

  153. Myrup, C. et al. Testicular cancer risk in first- and second-generation immigrants to Denmark. J. Natl Cancer Inst. 100, 41–47 (2008).

    Article  PubMed  Google Scholar 

  154. Nielsen, H., Nielsen, M. & Skakkebæk, N. E. The fine structure of a possible carcinoma-in-situ in the seminiferous tubules in the testis of four infertile men. APMIS 82, 235–248 (1974).

    CAS  Google Scholar 

  155. Almstrup, K. et al. Genomic and gene expression signature of the pre-invasive testicular carcinoma in situ. Cell Tissue Res. 322, 159–165 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Almstrup, K. et al. Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling. Cancer Res. 64, 4736–4743 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Moch, H., Cubilla, A. L., Humphrey, P. A., Reuter, V. E. & Ulbright, T. M. The 2016 WHO classification of tumours of the urinary system and male genital organs–part a: renal, penile, and testicular tumours. Eur. Urol. 70, 93–105 (2016).

    Article  PubMed  Google Scholar 

  158. Sharpe, R. M. & Skakkebæk, N. E. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertil. Steril. 89, e33–e38 (2008).

    Article  PubMed  Google Scholar 

  159. Lottrup, G. et al. Identification of a novel androgen receptor mutation in a family with multiple components compatible with the testicular dysgenesis syndrome. J. Clin. Endocrinol. Metab. 98, 2223–2229 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Depue, R. H., Pike, M. C. & Henderson, B. E. Cryptorchidism and testicular cancer. J. Natl Cancer Inst. 77, 830–832 (1986).

    Article  CAS  PubMed  Google Scholar 

  161. Moller, H. & Skakkebæk, N. E. Risks of testicular cancer and cryptorchidism in relation to socio-economic status and related factors: case-control studies in Denmark. Int. J. Cancer 66, 287–293 (1996).

    Article  CAS  PubMed  Google Scholar 

  162. Krabbe, S. et al. High incidence of undetected neoplasia in maldescended testes. Lancet 313, 999–1000 (1979).

    Article  Google Scholar 

  163. Serrano, T., Chevrier, C., Multigner, L., Cordier, S. & Jegou, B. International geographic correlation study of the prevalence of disorders of male reproductive health. Hum. Reprod. 28, 1974–1986 (2013).

    Article  CAS  PubMed  Google Scholar 

  164. Jørgensen, N. et al. East-West gradient in semen quality in the Nordic-Baltic area: a study of men from the general population in Denmark, Norway, Estonia and Finland. Hum. Reprod. 17, 2199–2208 (2002).

    Article  PubMed  Google Scholar 

  165. Berthelsen, J. G. & Skakkebæk, N. E. Gonadal function in men with testis cancer. Fertil. Steril. 39, 68–75 (1983).

    Article  CAS  PubMed  Google Scholar 

  166. Berthelsen, J. G. Andrological Aspects of Testicular Cancer 9–44 (Scriptor, 1984).

  167. Petersen, P. M. et al. Impaired testicular function in patients with carcinoma in situ of the testis. J. Clin. Oncol. 17, 173–179 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. Jacobsen, R. et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. Br. Med. J. 321, 789–792 (2000).

    Article  CAS  Google Scholar 

  169. Andersson, A. M. et al. Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys. J. Clin. Endocrinol. Metab. 92, 4696–4705 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Travison, T. G., Araujo, A. B., O’Donnell, A. B., Kupelian, V. & McKinlay, J. B. A population-level decline in serum testosterone levels in American men. J. Clin. Endocrinol. Metab. 92, 196–202 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Sharma, R., Harlev, A., Agarwal, A. & Esteves, S. C. Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen. Eur. Urol. 70, 635–645 (2016).

    Article  PubMed  Google Scholar 

  172. Jensen, T. K. et al. Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries. Am. J. Epidemiol. 159, 49–58 (2004).

    Article  PubMed  Google Scholar 

  173. Ramlau-Hansen, C. H. et al. Is prenatal exposure to tobacco smoking a cause of poor semen quality? A follow-up study. Am. J. Epidemiol. 165, 1372–1379 (2007).

    Article  PubMed  Google Scholar 

  174. Jensen, T. K. et al. Adult and prenatal exposures to tobacco smoke as risk indicators of fertility among 430 Danish couples. Am. J. Epidemiol. 148, 992–997 (1998).

    Article  CAS  PubMed  Google Scholar 

  175. Radin, R. G. et al. Active and passive smoking and fecundability in Danish pregnancy planners. Fertil. Steril. 102, 183–191.e2 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Sapra, K. J., Barr, D. B., Maisog, J. M., Sundaram, R. & Buck Louis, G. M. Time-to-pregnancy associated with couples’ use of tobacco products. Nicotine Tob. Res. 18, 2154–2161 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Wesselink, A. K. et al. Prospective study of cigarette smoking and fecundability. Hum. Reprod. 34, 558–567 (2019).

    Article  PubMed  Google Scholar 

  178. Holmboe, S. A. et al. Use of e-cigarettes associated with lower sperm counts in a cross-sectional study of young men from the general population. Hum. Reprod. 35, 1693–1701 (2020).

    Article  PubMed  Google Scholar 

  179. Gundersen, T. D. et al. Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men. Am. J. Epidemiol. 182, 473–481 (2015).

    Article  PubMed  Google Scholar 

  180. Nassan, F. L. et al. Marijuana smoking and markers of testicular function among men from a fertility centre. Hum. Reprod. 34, 715–723 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Jensen, T. K. et al. Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy. BMJ 317, 505–510 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ricci, E. et al. Semen quality and alcohol intake: a systematic review and meta-analysis. Reprod. Biomed. Online 34, 38–47 (2017).

    Article  CAS  PubMed  Google Scholar 

  183. Salas-Huetos, A., James, E. R., Aston, K. I., Jenkins, T. G. & Carrell, D. T. Diet and sperm quality: nutrients, foods and dietary patterns. Reprod. Biol. 19, 219–224 (2019).

    Article  PubMed  Google Scholar 

  184. Nassan, F. L. et al. Association of dietary patterns with testicular function in young Danish men. JAMA Netw. Open 3, e1921610 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Grieger, J. A. et al. Pre-pregnancy fast food and fruit intake is associated with time to pregnancy. Hum. Reprod. 33, 1063–1070 (2018).

    Article  PubMed  Google Scholar 

  186. Lee, S., Min, J. Y., Kim, H. J. & Min, K. B. Association between the frequency of eating non-home-prepared meals and women infertility in the United States. J. Prev. Med. Public Health 53, 73–81 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Hatch, E. E. et al. Intake of sugar-sweetened beverages and fecundability in a North American preconception cohort. Epidemiology 29, 369–378 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Supramaniam, P. R., Mittal, M., McVeigh, E. & Lim, L. N. The correlation between raised body mass index and assisted reproductive treatment outcomes: a systematic review and meta-analysis of the evidence. Reprod. Health 15, 34 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Mushtaq, R. et al. Effect of male body mass index on assisted reproduction treatment outcome: an updated systematic review and meta-analysis. Reprod. Biomed. Online 36, 459–471 (2018).

    Article  PubMed  Google Scholar 

  190. Sermondade, N. et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum. Reprod. Update 19, 221–231 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Ma, J. et al. Association between BMI and semen quality: an observational study of 3966 sperm donors. Hum. Reprod. 34, 155–162 (2019).

    Article  PubMed  Google Scholar 

  192. Vaamonde, D., Da Silva-Grigoletto, M. E., Garcia-Manso, J. M., Barrera, N. & Vaamonde-Lemos, R. Physically active men show better semen parameters and hormone values than sedentary men. Eur. J. Appl. Physiol. 112, 3267–3273 (2012).

    Article  CAS  PubMed  Google Scholar 

  193. Gaskins, A. J. et al. Physical activity and television watching in relation to semen quality in young men. Br. J. Sports Med. 49, 265–270 (2015).

    Article  PubMed  Google Scholar 

  194. Lalinde-Acevedo, P. C. et al. Physically active men show better semen parameters than their sedentary counterparts. Int. J. Fertil. Steril. 11, 156–165 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Sun, B. et al. Physical activity and sedentary time in relation to semen quality in healthy men screened as potential sperm donors. Hum. Reprod. 34, 2330–2339 (2019).

    Article  PubMed  Google Scholar 

  196. Hajizadeh Maleki, B. & Tartibian, B. Moderate aerobic exercise training for improving reproductive function in infertile patients: a randomized controlled trial. Cytokine 92, 55–67 (2017).

    Article  CAS  PubMed  Google Scholar 

  197. Ritchie, H. & Roser, M. Fossil fuels. Our World in Data https://ourworldindata.org/fossil-fuels (2020).

  198. Thompson, R. C., Moore, C. J., vom Saal, F. S. & Swan, S. H. Plastics, the environment and human health: current consensus and future trends. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 2153–2166 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Francis, M. About 7% of fossil fuels are consumed for non-combustion use in the United States. U.S. Energy Information System https://www.eia.gov/todayinenergy/detail.php?id=35672 (2018).

  200. Festel, G., Evans, D. & Jackson, B. Trade sustainability impact assessment for the negotiations of a partnership and cooperation agreement between the EU and China. https://trade.ec.europa.eu/doclib/docs/2008/september/tradoc_140583.pdf (2008).

  201. Woodruff, T. J., Zota, A. R. & Schwartz, J. M. Environmental chemicals in pregnant women in the US: NHANES 2003-2004. Environ. Health Perspect. 119, 878–885 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Rogan, W. J. et al. Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) in human milk: effects of maternal factors and previous lactation. Am. J. Public Health 76, 172–177 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Fang, J., Nyberg, E., Bignert, A. & Bergman, A. Temporal trends of polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls in mothers’ milk from Sweden, 1972-2011. Environ. Int. 60, 224–231 (2013).

    Article  PubMed  Google Scholar 

  204. Frederiksen, H. et al. UV filters in matched seminal fluid-, urine-, and serum samples from young men. J. Expo. Sci. Environ. Epidemiol. 31, 345–355 (2020).

    Article  PubMed  Google Scholar 

  205. Apel, P. et al. Time course of phthalate cumulative risks to male developmental health over a 27-year period: biomonitoring samples of the German Environmental Specimen Bank. Environ. Int. 137, 105467 (2020).

    Article  CAS  PubMed  Google Scholar 

  206. Lewtas, J. Air pollution combustion emissions: characterization of causative agents and mechanisms associated with cancer, reproductive, and cardiovascular effects. Mutat. Res. 636, 95–133 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Vohra, K. et al. Global mortality from outdoor fine particle pollution generated by fossil fuel combustion: results from GEOS-Chem. Environ. Res. 195, 110754 (2021).

    Article  CAS  PubMed  Google Scholar 

  208. Bamberger, M. et al. Surface water and groundwater analysis using aryl hydrocarbon and endocrine receptor biological assays and liquid chromatography-high resolution mass spectrometry in Susquehanna County, PA. Environ. Sci. Process. Impacts 21, 988–998 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Harville, E. W., Shankar, A., Zilversmit, L. & Buekens, P. The Gulf oil spill, miscarriage, and infertility: the GROWH study. Int. Arch. Occup. Environ. Health 91, 47–56 (2018).

    Article  PubMed  Google Scholar 

  210. Mocarelli, P., Brambilla, P., Gerthoux, P. M., Patterson, D. G. Jr & Needham, L. L. Change in sex ratio with exposure to dioxin. Lancet 348, 409–409 (1996).

    Article  CAS  PubMed  Google Scholar 

  211. Silva, M. J. et al. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ. Health Perspect. 112, 331–338 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Colborn, T. & Clement, C. Chemically-Induced Alterations in Sexual and Functional Development: the Wildlife/Human Connection (Princeton Scientific, 1992).

  213. Baskin, L. S., Himes, K. & Colborn, T. Hypospadias and endocrine disruption: is there a connection? Environ. Health Perspect. 109, 1175–1183 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Hauser, R. et al. Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European union. J. Clin. Endocrinol. Metab. 100, 1267–1277 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Rajpert-De Meyts, E., McGlynn, K. A., Okamoto, K., Jewett, M. A. & Bokemeyer, C. Testicular germ cell tumours. Lancet 387, 1762–1774 (2016).

    Article  PubMed  Google Scholar 

  216. Sallmén, M., Weinberg, C. R., Baird, D. D., Lindbohm, M. L. & Wilcox, A. J. Has human fertility declined over time? Why we may never know. Epidemiology 16, 494–499 (2005).

    Article  PubMed  Google Scholar 

  217. Joffe, M. et al. Studying time to pregnancy by use of a retrospective design. Am. J. Epidemiol. 162, 115–124 (2005).

    Article  PubMed  Google Scholar 

  218. Ahrenfeldt, L. J. et al. Heritability of subfertility among Danish twins. Fertil. Steril. 114, 618–627 (2020).

    Article  PubMed  Google Scholar 

  219. Buck, G. M. et al. Prospective pregnancy study designs for assessing reproductive and developmental toxicants. Environ. Health Perspect. 112, 79–86 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Scheike, T. H. & Keiding, N. Design and analysis of time-to-pregnancy. Stat. Methods Med. Res. 15, 127–140 (2006).

    Article  PubMed  Google Scholar 

  221. Slama, R. et al. Feasibility of the current-duration approach to studying human fecundity. Epidemiology 17, 440–449 (2006).

    Article  PubMed  Google Scholar 

  222. Hatch, E. E. et al. Evaluation of selection bias in an internet-based study of pregnancy planners. Epidemiology 27, 98–104 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  223. KOSIS. Vital statistics of Korea. https://kosis.kr/statHtml/statHtml.do?orgId=101&tblId=DT_1B8000F&language=en (2021).

  224. Leal, M. C. & França, L. R. The seminiferous epithelium cycle length in the black tufted-ear marmoset (Callithrix penicillata) is similar to humans. Biol. Reprod. 74, 616–624 (2006).

    Article  CAS  PubMed  Google Scholar 

  225. de Oliveira, C. F. A., Lara, N., Cardoso, B. R. L., de França, L. R. & de Avelar, G. F. Comparative testis structure and function in three representative mice strains. Cell Tissue Res. 382, 391–404 (2020).

    Article  PubMed  Google Scholar 

  226. Garner, D. L. & Hafez, E. S. E. Spermatozoa and seminal plasma. in Reproduction in Farm Animals (ed. Hafez, E. S. E.) 165–187 (Lea and Febiger, 1993).

  227. Valle Rdel, R. et al. Semen characteristics of captive common marmoset (Callithrix jacchus): a comparison of a German with a Brazilian colony. J. Med. Primatol. 43, 225–230 (2014).

    Article  PubMed  Google Scholar 

  228. Bezerra, M. J. B. et al. Major seminal plasma proteome of rabbits and associations with sperm quality. Theriogenology 128, 156–166 (2019).

    Article  CAS  PubMed  Google Scholar 

  229. Okamura, A. et al. Broken sperm, cytoplasmic droplets and reduced sperm motility are principal markers of decreased sperm quality due to organophosphorus pesticides in rats. J. Occup. Health 51, 478–487 (2009).

    Article  CAS  PubMed  Google Scholar 

  230. Prins, G. in Encyclopedia of Reproduction Vol. 4 (eds Knobil, E. & Neill, J. D.) 360–367 (Academic, 1998).

  231. Bhattacharjee, R. et al. Targeted disruption of glycogen synthase kinase 3A (GSK3A) in mice affects sperm motility resulting in male infertility. Biol. Reprod. 92, 65 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Harris, T., Marquez, B., Suarez, S. & Schimenti, J. Sperm motility defects and infertility in male mice with a mutation in Nsun7, a member of the Sun domain-containing family of putative RNA methyltransferases. Biol. Reprod. 77, 376–382 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Laversanne from the International Agency for Research on Cancer for assistance with the first draft of Fig. 4. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. The authors acknowledge financial support from the Innovation Fund Denmark, Danish Ministry of Environment (CEHOS), Danish Ministry of Health, The ReproUnion consortium/EU Interreg ÖKS, Brazilian institutions (CNPq and CAPES) and Minas Gerais State Foundation (FAPEMIG). Finally, the authors thank A. Wahlberg, Department of Anthropology, University of Copenhagen, and K. Kjær, GLOBE Institute, University of Copenhagen, for most valuable discussions prior to writing the paper.

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Authors and Affiliations

  1. Department of Growth and Reproduction, Copenhagen University Hospital — Rigshospitalet, Copenhagen, Denmark

    Niels E. Skakkebæk, Anna-Maria Andersson, Niels Jørgensen, Katharina M. Main, Lærke Priskorn, Stine A. Holmboe, Elvira V. Bräuner, Kristian Almstrup & Anders Juul

  2. International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Niels E. Skakkebæk, Anna-Maria Andersson, Niels Jørgensen, Katharina M. Main, Lærke Priskorn, Stine A. Holmboe, Elvira V. Bräuner, Kristian Almstrup & Anders Juul

  3. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Niels E. Skakkebæk, Katharina M. Main, Øjvind Lidegaard & Anders Juul

  4. Department of Public Health, University of Southern Denmark, Odense, Denmark

    Rune Lindahl-Jacobsen

  5. School of Public Health, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Hagai Levine

  6. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Øjvind Lidegaard

  7. Department of Morphology, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil

    Luiz R. Franca

  8. Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France

    Ariana Znaor

  9. Division of Environmental Sciences, Brunel University London, Uxbridge, UK

    Andreas Kortenkamp

  10. Division of Obstetrics and Gynaecology, University of Western Australia, Perth, Western Australia, Australia

    Roger J. Hart

  11. Fertility Specialists of Western Australia, Bethesda Hospital, Claremont, Western Australia, Australia

    Roger J. Hart

Authors
  1. Niels E. Skakkebæk
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  2. Rune Lindahl-Jacobsen
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  3. Hagai Levine
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  4. Anna-Maria Andersson
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  5. Niels Jørgensen
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  6. Katharina M. Main
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  7. Øjvind Lidegaard
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  8. Lærke Priskorn
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  9. Stine A. Holmboe
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  10. Elvira V. Bräuner
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  11. Kristian Almstrup
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  12. Luiz R. Franca
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  13. Ariana Znaor
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  14. Andreas Kortenkamp
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  15. Roger J. Hart
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  16. Anders Juul
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Contributions

N.E.S., R.L.-J., A.-M.A., S.A.H., E.V.B., K.A., L.R.F., A.Z., R.J.H. and A.J. researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. H.L., N.J., K.M.M., Ø.L. and A.K. contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. L.P. researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Niels E. Skakkebæk.

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Competing interests

R.J.H. is the Medical Director of Fertility Specialists of Western Australia and has equity interests in Western IVF. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks A.-S. Parent and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Databank, World Development Indicators: https://databank.worldbank.org/reports.aspx?source=world-development-indicators

Family Planning 2020: https://www.familyplanning2020.org/

Statistics Denmark: http://www.statistikbanken.dk/statbank5a/default.asp?w=1600

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Skakkebæk, N.E., Lindahl-Jacobsen, R., Levine, H. et al. Environmental factors in declining human fertility. Nat Rev Endocrinol 18, 139–157 (2022). https://doi.org/10.1038/s41574-021-00598-8

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