Relationship: 405



Malformation, Male reproductive tract leads to impaired, Fertility

Upstream event


Malformation, Male reproductive tract

Downstream event


impaired, Fertility

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Directness Weight of Evidence Quantitative Understanding
PPARα activation in utero leading to impaired fertility in males directly leads to Strong

Taxonomic Applicability


Term Scientific Term Evidence Link
rat Rattus norvegicus Strong NCBI
human Homo sapiens Strong NCBI
mice Mus sp. Weak NCBI

Sex Applicability


Life Stage Applicability


How Does This Key Event Relationship Work


Impairment in the normal development of the male reproductive tract (e.g. genital abnormality and/or cryptorchidism) can impact on fertility later in life.

Weight of Evidence


Biological Plausibility


Hypospadias next to cryptorchidism belongs to the most common male reproductive disorders that manifest at birth and may have a common origin in foetal life (Skakkebaek, Rajpert-De Meyts, and Main 2001) and are associated with decreased fertility (Thorup et al. 2010).

Empirical Support for Linkage



Asklund et al that semen quality was reduced in men with hypospadias and additional genital disorders, predominately cryptorchidism (Asklund et al. 2010). In another study by Bracka, 25% of 41 hypospadias patients including 26 patients also with cryptorchidism had a lower sperm density (Bracka 1989). Men with a history of cryptorchidism have an increased risk of infertility (Thorup et al. 2010). Eisenberg et al. found shorter AGD among infertile men as compared with fertile men (Eisenberg et al. 2011).


In rodents in utero exposure to agents known to disrupt androgen mediated pathways corrupts normal male genital development with a decrease in genital length (ie phallus length, AGD) and impaired testosterone and sperm production (Macleod et al. 2010), (Cowin et al. 2010), including exposure to phthalates (NTP 2005).

Uncertainties or Inconsistencies


Quantitative Understanding of the Linkage


Evidence Supporting Taxonomic Applicability


Human and Rat see "Empirical Support for Linkage"



Asklund, C, T K Jensen, K M Main, T Sobotka, N E Skakkebaek, and N Jørgensen. 2010. “Semen Quality, Reproductive Hormones and Fertility of Men Operated for Hypospadias.” International Journal of Andrology 33 (1) (February): 80–7. doi:10.1111/j.1365-2605.2009.00957.x.

Bracka, A. 1989. “A Long-Term View of Hypospadias.” British Journal of Plastic Surgery 42 (3) (May): 251–5.

Cowin, Prue A, Elspeth Gold, Jasna Aleksova, Moira K O’Bryan, Paul M D Foster, Hamish S Scott, and Gail P Risbridger. 2010. “Vinclozolin Exposure in Utero Induces Postpubertal Prostatitis and Reduces Sperm Production via a Reversible Hormone-Regulated Mechanism.” Endocrinology 151 (2) (February): 783–92. doi:10.1210/en.2009-0982.

Eisenberg, Michael L, Michael H Hsieh, Rustin Chanc Walters, Ross Krasnow, and Larry I Lipshultz. 2011. “The Relationship between Anogenital Distance, Fatherhood, and Fertility in Adult Men.” PloS One 6 (5) (January): e18973. doi:10.1371/journal.pone.0018973.

Macleod, D J, R M Sharpe, M Welsh, M Fisken, H M Scott, G R Hutchison, A J Drake, and S van den Driesche. 2010. “Androgen Action in the Masculinization Programming Window and Development of Male Reproductive Organs.” International Journal of Andrology 33 (2) (April): 279–87. doi:10.1111/j.1365-2605.2009.01005.x.

Mendiola, Jaime, Richard W Stahlhut, Niels Jørgensen, Fan Liu, and Shanna H Swan. 2011. “Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York.” Environmental Health Perspectives 119 (7) (July): 958–63. doi:10.1289/ehp.1103421.

NTP. 2005. “Multigenerational Reproductive Assessment by Continuous Breeding When Diethylhexylphthalate (CAS 117-81-7).”

Skakkebaek, N E, E Rajpert-De Meyts, and K M Main. 2001. “Testicular Dysgenesis Syndrome: An Increasingly Common Developmental Disorder with Environmental Aspects.” Human Reproduction (Oxford, England) 16 (5) (May): 972–8.

Thorup, Jorgen, Robert McLachlan, Dina Cortes, Tamara R. Nation, Adam Balic, Bridget R. Southwell, and John M. Hutson. 2010. “What Is New in Cryptorchidism and Hypospadias - A Critical Review on the Testicular Dysgenesis Hypothesis.” Journal of Pediatric Surgery. doi:10.1016/j.jpedsurg.2010.07.030.