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Relationship: 2125

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Reduction, Testosterone synthesis in Leydig cells leads to Decrease, testosterone levels

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, Testosterone synthesis in Leydig cells

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decrease, testosterone levels

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring	adjacent	High	Moderate	Cataia Ives (send email)	Under development: Not open for comment. Do not cite	Under Development
PPARα activation in utero leading to impaired fertility in males	adjacent	High		Arthur Author (send email)	Open for citation & comment	Under Review
PPARα activation leading to impaired fertility in adult male rodents	adjacent	High		Evgeniia Kazymova (send email)	Not under active development	Under Development
Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility	adjacent			Allie Always (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	High	NCBI
mice	Mus sp.	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Impairment of testosterone production in testes directly impacts on testosterone levels.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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 Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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 and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

See Table 1.

References

List of the literature that was cited for this KER description. More help

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.