API

Relationship: 608

Title

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Reduction, testosterone level leads to Malformation, Male reproductive tract

Upstream event

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Reduction, testosterone level

Downstream event

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Malformation, Male reproductive tract

Key Event Relationship Overview

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AOPs Referencing Relationship

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

Taxonomic Applicability

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

Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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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).

Weight of Evidence

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Biological Plausibility

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Hypospadias

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).

Cryptorchidism

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).

Empirical Support for Linkage

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Hypospadias

Reduced T production during the male rat development lead to hypospadias (Mylchreest, Cattley, and Foster 1998), (Mylchreest 2000), (Gray et al. 2000), (Parks 2000), (Wilson et al. 2004); this outcome is associated with Leydig cell function.

Anogential distance (AGD)

The decreased AGD has been associated with the perturbation of androgen-mediated development of the reproductive tract in rat males which were exposed to anti-androgens in utero (Wolf et al. 1999), (McIntyre et al. 2000), (McIntyre, Barlow, and Foster 2001). Several studies have demonstrated that exposure to phthalates results in decreased anogenital distance in human males (S. H. Swan et al. 2015), (Bornehag et al. 2015), presumably due to lowered testosterone levels (Suzuki et al. 2012), (Jurewicz and Hanke 2011), (Shanna H Swan et al. 2005), for details see Table 1.

     

KE: testosterone, reduction

KE: AGD, decreased

   

Compound

Species and strain: Doses: duration, [measurement day]

Effect level

   

Details

References

Phthalates

(DEHP)

rat, 0, 10, 30, 100, or 300 mg /kg bw/day : 7- 21 GD, [GD 21]

LOEL=-300 mg /kg bw/day

Testicular testosterone levels, reduction, no change plasma testosterone

   

(Borch et al. 2006)

Phthalates

(DEHP)

rat, GD 3- PND 21

LOEL=750 mg /kg bw/day

 

Anogenital distance decreased

Gestational and lactational

(Moore et al. 2001)

Phthalates

(DEHP)

rat

LOEL=750 mg /kg bw/day

reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male

Anogenital distance decreased

Exposure from (GD) 14 to postnatal day (PND) 3, AGD reduced by 36% in exposed male

(Parks 2000)

Phthalates

(DEHP)

rat

LOEL=15 mg /kg bw/day

Decreased testosterone levels

Effects on Sperm production

 

(Andrade et al. 2006)

Phthalates

(DEHP)

rat

LOEL=5 mg /kg bw/day

 

chryptorchidism

 

(Andrade et al. 2006)

Phthalates

(DEHP)

rat

LOEL=1.215 mg /kg bw/day

Decreased testosterone levels

Effects on Sperm production

 

(Andrade et al. 2006)

             

Phthalates

(DnHP)

rat

LOEL=250 mg /kg bw/day

 

Anogenital distance decreased

 

(Saillenfait, Gallissot, and Sabaté 2009)

Phthalates

(DEHP)

rat

LOEL=300 mg/kg/day

 

Anogenital distance decreased

 

(Jarfelt et al. 2005)

Phthalates

(DBP)

rat

LOEL=500 mg/kg/day

 

Anogenital distance decreased

throughout pregnancy until postnatal day 20

(Mylchreest, Cattley, and Foster 1998)

Phthalates

dicyclohexyl phthalate (DCHP)

rat

LOEL=6000 ppm

 

Anogenital distance decreased

F1 and F2 6000 ppm, and decrease of AGD and appearance of areola mammae were observed in the F1 male 6000 ppm and F2 male receiving doses of 1200 ppm or 6000 ppm.

(Hoshino, Iwai, and Okazaki 2005)

Phthalate (DBP)

rat

LOEL=500 mg/kg/day

intratesticular testosterone levels, reduction (by nearly 90%)

Anogenital distance decreased

GD 12 -20, examinations on GD20

(Johnson et al. 2011)

Phthalates

(MEHP)

Human

 

 

Anogenital index decreased

Urine concentration of phthalates metabolites MEHP associated with reduced AGI, suggestive association of sum of DEHP metabolites with reduced AGI

(Suzuki et al. 2012),

Phthalates (MEP), (MBP), (MBzP), (MiBP)

human

 

 

Urinary concentrations of phthalate metabolites inversely related to AGI

134 boys 2-36 months of age

(Shanna H Swan et al. 2005)

Phthalates

(MEHP, MBP)

human

MBP= 78.4 ng/mL* in urine; 85.2 ng/mL* in amniotic fluid

MEHP =24.9 ng/mL * in urine; 22.8 ng/mL* in amniotic fluid

 

In girls, decreased AGD in relation to amniotic fluid levels of MBP and MEHP. No associations found in boys

Amniotic fluid and urine concentrations of phthalate metabolites

(Huang et al. 2009)

Table 1 Summary of experimental evidence for the KER. Lowest-Observed-Effect-Level (LOEL), Dibutyl phthalate (DBP), diisobutyl phthalate (DiBP), di-n-hexyl phthalate (DnHP), monobutyl phthalate (MBP); Bis(2-ethylhexyl) phthalate (DEHP) mono-(2-ethylhexyl) phthalate (MEHP); monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP); anogenital index (AGI)-weight normalised index of AGD median.

Uncertainties or Inconsistencies

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Hypospadias

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).

Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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Hypospadias

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).

AGD

Across numerous species, including humans, AGD is longer in males compared to females; for review see (Barrett et al. 2014).

References

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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.

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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.

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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.

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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.