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Reduction of testosterone leads to Malformation, Male reproductive tract
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|PPARα activation in utero leading to impaired fertility in males||non-adjacent||High||Elise Grignard (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
Male sexual differentiation in general depends on testosterone (T), dihydrotestosterone (DHT), and the expression of androgen receptors by target cells (Manson and Carr 2003). Disturbances in the balance of this endocrine system by either endogenous or exogenous factors may lead to male reproductive tract, malformations (e.g. hypospadias, cryptorchidism). Reduction in T levels during foetal development subsequently lower levels of its metabolite DHT lead also to impaired growth of the perineum with reduced anogential distance (AGD) (Bowman et al. 2003).
Evidence Collection Strategy
Evidence Supporting this KER
The role of foetal androgens (T and DHT) is crucial for the development of the male reproductive tract especially during the first trimester of pregnancy. Androgens regulate masculinization of external genitalia. T is necessary for stabilization and differentiation of the Wolffian structures (e.g., the epididymis, vas deferens and seminal vesicles) and also for normal development of the foetal testes; DHT, produced locally from testosterone, is required for normal development of the genital tubercle and urogenital sinus into the external genitalia and prostate (Murashima et al. 2015). Therefore any defects in androgen biosynthesis, metabolism or action during development can cause hypospadias (Rey et al. 2005). The environmental factors with anti-androgenic activity may alter the complex regulation of male sex differentiation during foetal life (Kalfa et al., 2008). Although the cause in most cases is unknown, hypospadias has been associated with aberrant androgen signalling during development (Wolf et al. 1999). The aetiology of this frequent malformation has not been elucidated despite intensive investigation (Kalfa, Philibert, and Sultan 2009). Hypospadias thus appears at the crossroads of genetic, endocrine and environmental mechanisms (Kalfa, Philibert, and Sultan 2009).
Anogential distance (AGD)
The anogenital distance (AGD) is a sexual dimorphism that results from the sex difference in foetal androgen (DHT) levels (Rhees et al., 1997). The AGD is a marker of perineal growth and caudal migration of the genital tubercle. It is androgen-dependent in male rodents (Bowman et al. 2003). During development, androgens stimulate the growth of the perineal region between the sex papilla and the anus, resulting in an increased AGD in male offspring (Bowman et al. 2003). The AGD, is believed to be a biomarker of prenatal androgen exposure in many species, and in humans it has been associated with several adverse reproductive health outcomes in adults. AGD reflects foetal androgen exposure only within a discrete masculinization programming window (MPW), during which development of male reproductive organs is taking place (Wolf et al. 1999), (Macleod et al. 2010).
Undescended testis (UDT), also called cryptorchidism, is the most frequent congenital malformation in males, occurring in 2–5% of full-term male births (Hadziselimovic 2002) (Brucker-Davis et al. 2008). Testosterone and insulin-like peptide 3 (INSL3) are two major Leydig cell hormones that regulate physiological testicular descent during foetal development (Virtanen et al. 2007). Most cases of cryptorchidism remain idiopathic but epidemiological and experimental studies have suggested a role of both genetic and environmental factors. Studies e. g.(Gray et al. 2000) have shown that maternal administration of certain chemicals (phthalate esters) during the critical intrauterine period of sexual differentiation alters development of both androgen- and insl3-dependent tissues. Cryptorchidism is shown to be linked with increased risk of hypofertility and testicular cancer (Fénichel et al. 2015).
Uncertainties and Inconsistencies
Epidemiological studies have demonstrated an association between foetal estrogen exposure and hypospadias (Klip et al. 2002), (Brouwers et al. 2007). However, the molecular mechanism underlying this association is unknown (Wang and Baskin 2008), (Blaschko, Cunha, and Baskin 2012).
Anogential distance (AGD)
Study by Huang et al did not found associations with the phthalates metabolites in the male AGD, however in females in relation to amniotic fluid levels of MBP and MEHP (Huang et al. 2009).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Maternal exposure to estrogenic and antiandrogenic endocrine disrupting compounds has been implicated in increased risk of cryptorchidism and hypospadias in human male offspring without statistical significance (Morales-Suárez-Varela et al. 2011).
Across numerous species, including humans, AGD is longer in males compared to females; for review see (Barrett et al. 2014).
Andrade, Anderson J M, Simone W Grande, Chris E Talsness, Konstanze Grote, and Ibrahim Chahoud. 2006. “A Dose-Response Study Following in Utero and Lactational Exposure to Di-(2-Ethylhexyl)-Phthalate (DEHP): Non-Monotonic Dose-Response and Low Dose Effects on Rat Brain Aromatase Activity.” Toxicology 227 (3) (October 29): 185–92. doi:10.1016/j.tox.2006.07.022. http://www.ncbi.nlm.nih.gov/pubmed/16949715.
Barrett, Emily S, Lauren E Parlett, J Bruce Redmon, and Shanna H Swan. 2014. “Evidence for Sexually Dimorphic Associations between Maternal Characteristics and Anogenital Distance, a Marker of Reproductive Development.” American Journal of Epidemiology 179 (1) (January 1): 57–66. doi:10.1093/aje/kwt220. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3864710&tool=pmcentrez&rendertype=abstract.
Blaschko, Sarah D, Gerald R Cunha, and Laurence S Baskin. 2012. “Molecular Mechanisms of External Genitalia Development.” Differentiation; Research in Biological Diversity 84 (3) (October): 261–8. doi:10.1016/j.diff.2012.06.003. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3443292&tool=pmcentrez&rendertype=abstract.
Borch, Julie, Stine Broeng Metzdorff, Anne Marie Vinggaard, Leon Brokken, and Majken Dalgaard. 2006. “Mechanisms Underlying the Anti-Androgenic Effects of Diethylhexyl Phthalate in Fetal Rat Testis.” Toxicology 223 (1-2) (June 1): 144–55. doi:10.1016/j.tox.2006.03.015. http://www.sciencedirect.com/science/article/pii/S0300483X0600165X.
Bornehag, Carl-Gustaf, Fredrik Carlstedt, Bo Ag Jönsson, Christian H Lindh, Tina K Jensen, Anna Bodin, Carin Jonsson, Staffan Janson, and Shanna H Swan. 2015. “Prenatal Phthalate Exposures and Anogenital Distance in Swedish Boys.” Environmental Health Perspectives 123 (1) (January): 101–7. doi:10.1289/ehp.1408163. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4286276&tool=pmcentrez&rendertype=abstract.
Bowman, Christopher J, Norman J Barlow, Katie J Turner, Duncan G Wallace, and Paul M D Foster. 2003. “Effects of in Utero Exposure to Finasteride on Androgen-Dependent Reproductive Development in the Male Rat.” Toxicological Sciences : An Official Journal of the Society of Toxicology 74 (2) (August): 393–406. doi:10.1093/toxsci/kfg128. http://www.ncbi.nlm.nih.gov/pubmed/12773767.
Brouwers, Marijn M, Wouter F J Feitz, Luc A J Roelofs, Lambertus A L M Kiemeney, Robert P E de Gier, and Nel Roeleveld. 2007. “Risk Factors for Hypospadias.” European Journal of Pediatrics 166 (7) (July): 671–8. doi:10.1007/s00431-006-0304-z. http://www.ncbi.nlm.nih.gov/pubmed/17103190.
Brucker-Davis, Françoise, Kathy Wagner-Mahler, Isabelle Delattre, Béatrice Ducot, Patricia Ferrari, André Bongain, Jean-Yves Kurzenne, Jean-Christophe Mas, and Patrick Fénichel. 2008. “Cryptorchidism at Birth in Nice Area (France) Is Associated with Higher Prenatal Exposure to PCBs and DDE, as Assessed by Colostrum Concentrations.” Human Reproduction (Oxford, England) 23 (8) (August): 1708–18. doi:10.1093/humrep/den186. http://www.ncbi.nlm.nih.gov/pubmed/18503055.
Eisenberg, Michael L, Tina K Jensen, R Chanc Walters, Niels E Skakkebaek, and Larry I Lipshultz. 2011. “The Relationship between Anogenital Distance and Reproductive Hormone Levels in Adult Men.” The Journal of Urology 187 (2) (February): 594–8. doi:10.1016/j.juro.2011.10.041. http://www.ncbi.nlm.nih.gov/pubmed/22177168.
Fénichel, Patrick, Najiba Lahlou, Patrick Coquillard, Patricia Panaïa-Ferrari, Kathy Wagner-Mahler, and Françoise Brucker-Davis. 2015. “Cord Blood Insulin-like Peptide 3 (INSL3) but Not Testosterone Is Reduced in Idiopathic Cryptorchidism.” Clinical Endocrinology 82 (2) (February): 242–7. doi:10.1111/cen.12500. http://www.ncbi.nlm.nih.gov/pubmed/24826892.
Gray, L E, J Ostby, J Furr, M Price, D N Veeramachaneni, and L Parks. 2000. “Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat.” Toxicological Sciences : An Official Journal of the Society of Toxicology 58 (2) (December): 350–65. http://www.ncbi.nlm.nih.gov/pubmed/11099647.
Hadziselimovic, F. 2002. “Cryptorchidism, Its Impact on Male Fertility.” European Urology 41 (2) (February): 121–3. http://www.ncbi.nlm.nih.gov/pubmed/12074397. Hoshino, Nobuhito, Mayumi Iwai, and Yoshimasa Okazaki. 2005. “A Two-Generation Reproductive Toxicity Study of Dicyclohexyl Phthalate in Rats.” The Journal of Toxicological Sciences 30 Spec No (December): 79–96. http://www.ncbi.nlm.nih.gov/pubmed/16641545.
Huang, Po-Chin, Pao-Lin Kuo, Yen-Yin Chou, Shio-Jean Lin, and Ching-Chang Lee. 2009. “Association between Prenatal Exposure to Phthalates and the Health of Newborns.” Environment International 35 (1) (January): 14–20. doi:10.1016/j.envint.2008.05.012. http://www.ncbi.nlm.nih.gov/pubmed/18640725. Jarfelt, Kirsten, Majken Dalgaard, Ulla Hass, Julie Borch, Helene Jacobsen, and Ole Ladefoged. 2005. “Antiandrogenic Effects in Male Rats Perinatally Exposed to a Mixture of di(2-Ethylhexyl) Phthalate and di(2-Ethylhexyl) Adipate.” Reproductive Toxicology (Elmsford, N.Y.) 19 (4): 505–15. doi:10.1016/j.reprotox.2004.11.005. http://www.ncbi.nlm.nih.gov/pubmed/15749265.
Johnson, Kamin J, Erin N McDowell, Megan P Viereck, and Jessie Q Xia. 2011. “Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways.” Toxicological Sciences : An Official Journal of the Society of Toxicology 120 (2) (April): 460–74. doi:10.1093/toxsci/kfr020. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3061485&tool=pmcentrez&rendertype=abstract.
Jurewicz, Joanna, and Wojciech Hanke. 2011. “Exposure to Phthalates: Reproductive Outcome and Children Health. A Review of Epidemiological Studies.” International Journal of Occupational Medicine and Environmental Health 24 (2) (June): 115–41. doi:10.2478/s13382-011-0022-2. http://www.ncbi.nlm.nih.gov/pubmed/21594692. Kalfa, Nicolas, Pascal Philibert, and Charles Sultan. 2009. “Is Hypospadias a Genetic, Endocrine or Environmental Disease, or Still an Unexplained Malformation?” International Journal of Andrology 32 (3) (June): 187–97. doi:10.1111/j.1365-2605.2008.00899.x. http://www.ncbi.nlm.nih.gov/pubmed/18637150.
Klip, Helen, Janneke Verloop, Jan D van Gool, Marlies E T A Koster, Curt W Burger, and Flora E van Leeuwen. 2002. “Hypospadias in Sons of Women Exposed to Diethylstilbestrol in Utero: A Cohort Study.” Lancet 359 (9312) (March 30): 1102–7. doi:10.1016/S0140-6736(02)08152-7. http://www.ncbi.nlm.nih.gov/pubmed/11943257.
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. http://www.ncbi.nlm.nih.gov/pubmed/20002220. Manson, Jeanne M, and Michael C Carr. 2003. “Molecular Epidemiology of Hypospadias: Review of Genetic and Environmental Risk Factors.” Birth Defects Research. Part A, Clinical and Molecular Teratology 67 (10) (October): 825–36. doi:10.1002/bdra.10084. http://www.ncbi.nlm.nih.gov/pubmed/14745936.
McIntyre, B S, N J Barlow, and P M Foster. 2001. “Androgen-Mediated Development in Male Rat Offspring Exposed to Flutamide in Utero: Permanence and Correlation of Early Postnatal Changes in Anogenital Distance and Nipple Retention with Malformations in Androgen-Dependent Tissues.” Toxicological Sciences : An Official Journal of the Society of Toxicology 62 (2) (August): 236–49. http://www.ncbi.nlm.nih.gov/pubmed/11452136.
McIntyre, B S, N J Barlow, D G Wallace, S C Maness, K W Gaido, and P M Foster. 2000. “Effects of in Utero Exposure to Linuron on Androgen-Dependent Reproductive Development in the Male Crl:CD(SD)BR Rat.” Toxicology and Applied Pharmacology 167 (2) (September 1): 87–99. doi:10.1006/taap.2000.8998. http://www.ncbi.nlm.nih.gov/pubmed/10964759.
Moore, R W, T A Rudy, T M Lin, K Ko, and R E Peterson. 2001. “Abnormalities of Sexual Development in Male Rats with in Utero and Lactational Exposure to the Antiandrogenic Plasticizer Di(2-Ethylhexyl) Phthalate.” Environmental Health Perspectives 109 (3) (March): 229–37. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1240240&tool=pmcentrez&rendertype=abstract.
Morales-Suárez-Varela, María M, Gunnar V Toft, Morten S Jensen, Cecilia Ramlau-Hansen, Linda Kaerlev, Ane-Marie Thulstrup, Agustín Llopis-González, Jørn Olsen, and Jens P Bonde. 2011. “Parental Occupational Exposure to Endocrine Disrupting Chemicals and Male Genital Malformations: A Study in the Danish National Birth Cohort Study.” Environmental Health : A Global Access Science Source 10 (1) (January): 3. doi:10.1186/1476-069X-10-3. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3033238&tool=pmcentrez&rendertype=abstract.
Murashima, Aki, Satoshi Kishigami, Axel Thomson, and Gen Yamada. 2015. “Androgens and Mammalian Male Reproductive Tract Development.” Biochimica et Biophysica Acta 1849 (2) (February): 163–170. doi:10.1016/j.bbagrm.2014.05.020. http://www.sciencedirect.com/science/article/pii/S1874939914001266.
Mylchreest, Eve. 2000. “Dose-Dependent Alterations in Androgen-Regulated Male Reproductive Development in Rats Exposed to Di(n-Butyl) Phthalate during Late Gestation.” Toxicological Sciences 55 (1) (May 1): 143–151. doi:10.1093/toxsci/55.1.143. http://www.toxsci.oupjournals.org/cgi/doi/10.1093/toxsci/55.1.143.
Mylchreest, Eve, Russell C. Cattley, and Paul M. D. Foster. 1998. “Male Reproductive Tract Malformations in Rats Following Gestational and Lactational Exposure to Di( N -Butyl) Phthalate: An Antiandrogenic Mechanism?” Toxicological Sciences 43 (1) (May 1): 47–60. doi:10.1093/toxsci/43.1.47. http://toxsci.oxfordjournals.org/content/43/1/47.short?rss=1&ssource=mfc.
Parks, L. G. 2000. “The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis during Sexual Differentiation in the Male Rat.” Toxicological Sciences 58 (2) (December 1): 339–349. doi:10.1093/toxsci/58.2.339. http://toxsci.oxfordjournals.org/content/58/2/339.abstract.
Rey, Rodolfo A, Ethel Codner, Germán Iñíguez, Patricia Bedecarrás, Romina Trigo, Cecilia Okuma, Silvia Gottlieb, Ignacio Bergadá, Stella M Campo, and Fernando G Cassorla. 2005. “Low Risk of Impaired Testicular Sertoli and Leydig Cell Functions in Boys with Isolated Hypospadias.” The Journal of Clinical Endocrinology and Metabolism 90 (11) (November): 6035–40. doi:10.1210/jc.2005-1306. http://www.ncbi.nlm.nih.gov/pubmed/16131574.
Saillenfait, Anne-Marie, Frédéric Gallissot, and Jean-Philippe Sabaté. 2009. “Differential Developmental Toxicities of Di-N-Hexyl Phthalate and Dicyclohexyl Phthalate Administered Orally to Rats.” Journal of Applied Toxicology : JAT 29 (6) (August): 510–21. doi:10.1002/jat.1436. http://www.ncbi.nlm.nih.gov/pubmed/19391110.
Suzuki, Y, J Yoshinaga, Y Mizumoto, S Serizawa, and H Shiraishi. 2012. “Foetal Exposure to Phthalate Esters and Anogenital Distance in Male Newborns.” International Journal of Andrology 35 (3) (June): 236–44. doi:10.1111/j.1365-2605.2011.01190.x. http://www.ncbi.nlm.nih.gov/pubmed/21696396.
Swan, S. H., S. Sathyanarayana, E. S. Barrett, S. Janssen, F. Liu, R. H. N. Nguyen, and J. B. Redmon. 2015. “First Trimester Phthalate Exposure and Anogenital Distance in Newborns.” Human Reproduction 30 (4) (February 18): 963–72. doi:10.1093/humrep/deu363. http://www.ncbi.nlm.nih.gov/pubmed/25697839.
Swan, Shanna H, Katharina M Main, Fan Liu, Sara L Stewart, Robin L Kruse, Antonia M Calafat, Catherine S Mao, et al. 2005. “Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure.” Environmental Health Perspectives 113 (8) (August): 1056–61. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1280349&tool=pmcentrez&rendertype=abstract.
Virtanen, Helena E, Dina Cortes, Ewa Rajpert-De Meyts, E Martin Ritzén, Agneta Nordenskjöld, Niels E Skakkebaek, and Jorma Toppari. 2007. “Development and Descent of the Testis in Relation to Cryptorchidism.” Acta Paediatrica (Oslo, Norway : 1992) 96 (5) (May): 622–7. doi:10.1111/j.1651-2227.2007.00244.x. http://www.ncbi.nlm.nih.gov/pubmed/17462055.
Wang, Ming-Hsien, and Laurence S Baskin. 2008. “Endocrine Disruptors, Genital Development, and Hypospadias.” Journal of Andrology 29 (5): 499–505. doi:10.2164/jandrol.108.004945. http://www.ncbi.nlm.nih.gov/pubmed/18497336.
Wilson, Vickie S, Christy Lambright, Johnathan Furr, Joseph Ostby, Carmen Wood, Gary Held, and L Earl Gray. 2004. “Phthalate Ester-Induced Gubernacular Lesions Are Associated with Reduced insl3 Gene Expression in the Fetal Rat Testis.” Toxicology Letters 146 (3) (March 2): 207–15. http://www.ncbi.nlm.nih.gov/pubmed/14687758.
Wolf, C., C. Lambright, P. Mann, M. Price, R. L. Cooper, J. Ostby, and L. E. Gray. 1999. “Administration of Potentially Antiandrogenic Pesticides (procymidone, Linuron, Iprodione, Chlozolinate, P,p’-DDE, and Ketoconazole) and Toxic Substances (dibutyl- and Diethylhexyl Phthalate, PCB 169, and Ethane Dimethane Sulphonate) during Sexual Differen.” Toxicology and Industrial Health 15 (1-2) (February 1): 94–118. doi:10.1177/074823379901500109. http://tih.sagepub.com/content/15/1-2/94.abstract?ijkey=9190cbc3a5effe489f5f27911b833ff5e3f1a689&keytype2=tf_ipsecsha.