API

Relationship: 439

Title

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Reduction, Testosterone synthesis in Leydig cells leads to Reduction, testosterone level

Upstream event

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Reduction, Testosterone synthesis in Leydig cells

Downstream event

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Reduction, testosterone level

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus Strong NCBI
human Homo sapiens Strong NCBI
mice Mus sp. Moderate 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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Impairment of testosterone production in testes directly impacts on testosterone levels.

Weight of Evidence

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Biological Plausibility

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Within the testes, steroid synthesis takes place within the mitochondria of Leydig cells. Testosterone production by Leydig cells is primarily under the control of LH. LH indirectly stimulates the transfer of cholesterol into the mitochondrial matrix to cholesterol side-chain cleavage cytochrome P450 (P450scc, CYP11A), which converts cholesterol to pregnenolone. Pregnenolone diffuses to the smooth endoplasmic reticulum where it is further metabolized to testosterone via the actions of 3β-hydroxysteroid dehydrogenase Δ5-Δ4-isomerase (3β-HSD), 17α-hydroxylase/C17-20 lyase (P450c17, CYP17), and 17β-hydroxysteroid dehydrogenase type III (17HSD3). For review see (Payne & Hales, 2013). Therefore, inhibition or impairment of the testosterone production directly impacts on the levels of testosterone.

Empirical Support for Linkage

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There is evidence from experimental work that demonstrates a coordinated, dose-dependent reduction in the production of testosterone and consecutive reduction of testosterone levels in foetal testes and in serum, see Table 1.

 

 

 

KE: testosterone synthesis, reduction

KE: testosterone, reduction

 

 

Compound

Species

Effect level

 

 

Details

References

Phthalates

(DEHP)

rat

LOEL =300 mg/kg/day

testicular testosterone production, reduction (ex vivo)

testicular testosterone levels, reduction, no change plasma testosterone

testosterone levels at GD 21 in male rat fetuses exposed to 0, 10, 30, 100, or 300 mg /kg bw/day from GD 7 to GD 21 testicular testosterone production ex vivo

(Borch, Metzdorff, Vinggaard, Brokken, & Dalgaard, 2006)

Phthalates

(DBP)

rat

LOEL =50 mg/kg/day

 

testicular testosterone levels, reduction,

Testicular testosterone was reduced >50 mg/kg/day

(Shultz, 2001)

Phthalates

(DEHP)

rat

LOEL=300 mg/kg/day

fetal testicular testosterone production, reduction

 

 

(Borch, Ladefoged, Hass, & Vinggaard, 2004)

 

Phthalates

(DEHP)

rat

LOEL=300 mg/kg/day

 

testicular testosterone levels, reduction,

 

(Borch et al., 2004)

 

Phthalates

(DEHP)

rat

LOEL=300 mg/kg/day

 

No change plasma testosterone

 

(Borch et al., 2004)

 

Phthalates

(DEHP)

rat

LOEL=100 mg/kg/day

 

Serum testosterone levels, reduction,

 

(Akingbemi, 2001)

 

Phthalates

(DEHP)

rat

LOEL=750 mg /kg /day

 

testicular testosterone levels, reduction, by 60 – 85%

 

(Parks, 2000)

Phthalates

(DEHP)

rat

LOEL=750 mg /kg/day

 

testosterone levels, reduction, fetuses on GD 17 (71% lower than controls) and 18 (47% lower than controls)

 

(Parks, 2000)

 

Phthalates

(DEHP)

rat

LOEL=750mg/kg/day

 

ex vivo testosterone production, reduction by 50%

 

 

(Wilson et al., 2004)

 

Phthalates

(DEHP)

rat

LOEL=234 mg/kg/day

 

 

serum testosterone levels, reduction,

 

(Culty et al., 2008)

 

Phthalates

(DEHP)

rat

LOEL=1250 mg/kg/day

ex vivo foetal testicular production

 

 

(Culty et al., 2008)

 

Phthalates

(DEHP)

rat

ED50=444,2 mg/kg/day

ex vivo foetal testicular production, reduction

 

 

 

 


(Hannas et al., 2012)

 

Phthalates

(DHP)

rat

ED50=75.25 mg/kg/day

 

ex vivo foetal testicular production, reduction

 

 

(Hannas et al., 2012)

 

Table 1. Summary table for empirical support for this KER. ED50 - half maximal effective concentration, LOEL- lowest observed effect level, Dibutyl phthalate (DBP), Bis(2-ethylhexyl) phthalate (DEHP), Dihexyl Phthalate (DHP).

Uncertainties or Inconsistencies

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Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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Ses Table 1.

References

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Akingbemi, B. T. 2001. “Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate.” Biology of Reproduction 65 (4) (October 1): 1252–1259. doi:10.1095/biolreprod65.4.1252.

Borch, Julie, Ole Ladefoged, Ulla Hass, and Anne Marie Vinggaard. 2004. “Steroidogenesis in Fetal Male Rats Is Reduced by DEHP and DINP, but Endocrine Effects of DEHP Are Not Modulated by DEHA in Fetal, Prepubertal and Adult Male Rats.” Reproductive Toxicology (Elmsford, N.Y.) 18 (1): 53–61. doi:10.1016/j.reprotox.2003.10.011.

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.

Culty, Martine, Raphael Thuillier, Wenping Li, Yan Wang, Daniel B Martinez-Arguelles, Carolina Gesteira Benjamin, Kostantinos M Triantafilou, Barry R Zirkin, and Vassilios Papadopoulos. 2008. “In Utero Exposure to Di-(2-Ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat.” Biology of Reproduction 78 (6) (June): 1018–28. doi:10.1095/biolreprod.107.065649.

Hannas, Bethany R, Christy S Lambright, Johnathan Furr, Nicola Evans, Paul M D Foster, Earl L Gray, and Vickie S Wilson. 2012. “Genomic Biomarkers of Phthalate-Induced Male Reproductive Developmental Toxicity: A Targeted RT-PCR Array Approach for Defining Relative Potency.” Toxicological Sciences : An Official Journal of the Society of Toxicology 125 (2) (February): 544–57. doi:10.1093/toxsci/kfr315.

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.

Shultz, V. D. 2001. “Altered Gene Profiles in Fetal Rat Testes after in Utero Exposure to Di(n-Butyl) Phthalate.” Toxicological Sciences 64 (2) (December 1): 233–242. doi:10.1093/toxsci/64.2.233.

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) (February): 207–215. doi:10.1016/j.toxlet.2003.09.012.