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AOP: 18


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

PPARα activation in utero leading to impaired fertility in males

Short name
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PPARα activation leading to impaired fertility
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v1.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Malgorzata Nepelska, Elise Grignard, Sharon Munn,

Systems Toxicology Unit, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Via E. Fermi 2749, I-21027 Ispra, Varese, Italy

Corresponding author:;

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)


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  • Elise Grignard
  • Arthur Author


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
1.21 Under Review
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Activation, PPARα December 28, 2020 12:48
impaired, Fertility September 14, 2023 12:10
Decrease, Steroidogenic acute regulatory protein (STAR) September 16, 2017 10:14
Reduction, Cholesterol transport in mitochondria September 16, 2017 10:14
Reduction, Testosterone synthesis in Leydig cells September 16, 2017 10:14
Decrease, Translocator protein (TSPO) September 16, 2017 10:14
Malformation, Male reproductive tract September 16, 2017 10:14
Decrease, testosterone levels May 24, 2024 12:27
Decrease, Steroidogenic acute regulatory protein (STAR) leads to Reduction, Cholesterol transport in mitochondria December 02, 2016 09:28
Reduction, Cholesterol transport in mitochondria leads to Reduction, Testosterone synthesis in Leydig cells December 02, 2016 10:16
Reduction, Testosterone synthesis in Leydig cells leads to Decrease, testosterone levels May 01, 2024 16:10
Activation, PPARα leads to Decrease, Steroidogenic acute regulatory protein (STAR) December 02, 2016 10:12
Decrease, Translocator protein (TSPO) leads to Reduction, Cholesterol transport in mitochondria December 02, 2016 10:14
Activation, PPARα leads to Decrease, Translocator protein (TSPO) December 02, 2016 10:13
Malformation, Male reproductive tract leads to impaired, Fertility December 02, 2016 10:21
Decrease, testosterone levels leads to Malformation, Male reproductive tract May 01, 2024 16:16


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP links the activation of Peroxisome Proliferator Activated Receptor α (PPARα) to the developmental/reproductive toxicity in male. The development of this AOP relies on evidence collected from rodent models and incorporates human mechanistic and epidemiological data. The PPARα is a ligand-activated transcription factor that belongs to the nuclear receptor family, which also includes the steroid and thyroid hormone receptors. The hypothesis that PPARα action is the mechanistic basis for effects on the reproductive system arises from limited experimental data indicating relationships between activation of this receptor and impairment of steroidogenesis leading to reproductive toxicity. PPARs play important roles in the metabolic regulation of lipids, of which cholesterol, in particular, being a precursor of steroid hormones, makes the link between lipid metabolism to effects on reproduction. The key events in the pathway comprise the activation of PPARα, followed by the disruption cholesterol transport in mitochondria, impairment of hormonal balance which leads to malformation of the reproductive tract in males which may lead to impaired fertility. The PPARα-initiated AOP to rodent male developmental toxicity is a first step for structuring current knowledge about a mode of action which is neither AR-mediated nor via direct steroidogenesis enzymes inhibition. In the current form the pathway lays a strong basis for linking an endocrine mode of action with an apical endpoint, a prerequisite requirement for the identification of endocrine disrupting chemicals. This AOP is complemented with a structured data collection which will serve as the basis for further quantitative development of the pathway.

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 227 Activation, PPARα Activation, PPARα
KE 266 Decrease, Steroidogenic acute regulatory protein (STAR) Decrease, Steroidogenic acute regulatory protein (STAR)
KE 447 Reduction, Cholesterol transport in mitochondria Reduction, Cholesterol transport in mitochondria
KE 413 Reduction, Testosterone synthesis in Leydig cells Reduction, Testosterone synthesis in Leydig cells
KE 1690 Decrease, testosterone levels Decrease, testosterone levels
KE 289 Decrease, Translocator protein (TSPO) Decrease, Translocator protein (TSPO)
AO 406 impaired, Fertility impaired, Fertility
AO 348 Malformation, Male reproductive tract Malformation, Male reproductive tract

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Development High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Low NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Biological plausibility, coherence, and consistency of the experimental evidence

In the presented AOP it is hypothesized that the key events occur in a biologically plausible order prior to the development of adverse outcomes. The PPARα activators have been shown to alter steroidogenesis and impair reproduction [see reviews (Corton and Lapinskas 2004), (Latini et al. 2008), (David 2006)]. However, there are some conflicting reports on the involvement of PPARα as MIE of the proposed AOP (Johnson, Heger, and Boekelheide 2012), (David 2006). The biochemistry of steroidogenesis and the predominant role of the gonad in synthesis of the sex steroids are well established. Steroidogenesis is a complex process that is dependent on the availability of cholesterol in mitochondria. Perturbation of genes responsible for cholesterol transport and steroidogenic enzyme activities in the Leydig cell will lead to a decrease in testicular testosterone (T) production. As a consequence, androgen-dependent tissue differentiation/development is adversely affected. The physical manifestation of this event may be reproductive tract malformation and possibly leads to impaired fertility.

Concordance of dose-response relationships

This is a qualitative description of the pathway; the currently available studies provide quantitative information on dose-response relationships only partially. Experimental data are based on exposure to phthalates and indicate that key events of this pathway occur at similar dose levels. The effects of altered gene expression levels that are responsible for the cholesterol transport into the Leydig cells were shown at >50 mg/kg/bw, a dose at which foetal T was decreased and anatomical malformations (hypospadias) were produced (Mylchreest, Cattley, and Foster 1998), (Mylchreest 2000), (Akingbemi 2001), (Lehmann et al. 2004). Tailored experiments are required for the exploration of quantitative linkages.

Temporal concordance among the key events and the adverse outcome

This AOP bridges two life stages: the AOs are results of the chemical exposure during a critical prenatal period for male development, the masculinization programming window (MPW), within which androgens must act to ensure the correct development of the male reproductive tract (Welsh et al. 2008). Therefore, the AOP focuses on the exposures within the MPW (15.5–18.5 GD days in rats). The temporal relationship of exposure to gestation day has been investigated using phthalates and it has been demonstrated that the gestational timing of exposure is important for the production of the adverse effects on the male reproductive tract (reviewed in (Ema 2002)). Moreover, the temporal relationship between alterations of gene expression and changes in testosterone production has been investigated for phthalates (DBP) (Lehmann et al. 2004), (Thompson et al. 2005). Initial increases in gene expression are followed by decreases in the expression of genes which are associated with steroidogenesis. The observed decreased steroidogenesis and subsequent decrease in testosterone levels is well established as precursors to anatomical changes in the developing male reproductive tract. Thus, those key events of gene expression are temporally consistent with subsequent events, however complete temporal concordance studies are missing.

Strength, consistency, and specificity of association of adverse effect and initiating event

The strength of the chosen chemical initiators as PPARα activators was shown to partially correlate with their ability to act as a male reproductive toxicant (Corton and Lapinskas 2004). The presented key events leading to a decrease in steroidogenesis are plausible and consistent with the observed effects. There is coherence between decreased testosterone synthesis and malformations.

Alternative mechanism(s) or MIE(s) described which may contribute/synergise the postulated AOP

The inhibitory effect of PPARα activation seems to be attributable to an impairment of the multistep process of cholesterol mobilization, transport into mitochondria, and steroidogenesis leading to impaired androgens production. Therefore, it is plausible that several other mechanisms may contribute to/synergise with this AOP. For example, activation of other isoforms of PPARs (PPARβ/δ or/and γ) is hypothesised to be relevant for the pathway (Lapinskas et al. 2005), (Shipley and Waxman 2004).

PPARγ activation

Opposing effects of PPARγ ligands (thiazolidinediones, TZD) on androgen levels and/or production in male humans (Dunaif et al. 1996), (Bloomgarden, Futterweit, and Poretsky 2001), (Vierhapper, Nowotny, and Waldhäusl 2003) and animal models have been described (Kempná et al. 2007), (Gasic et al. 1998), (Mu et al. 2000), (Arlt, Auchus, and Miller 2001), (Minge, Robker, and Norman 2008), (Gasic et al. 2001), (Veldhuis, Zhang, and Garmey 2002). In rats no effects of PPARγ ligand (rosiglitazone) on production or total circulating testosterone levels were seen (Boberg et al. 2008), however a decrease in basal or induced testosterone production occurred in the Leydig cells of rosiglitazone-treated rats (Couto et al. 2010).

Moreover, there are contradicting reports as to the presence of PPARγ in the foetal testes (Hannas et al. 2012). Few others transcription factors involved in regulation of lipid metabolism are hypothesized to mediate effects on fetal Leydig cell gene expression like sterol regulatory element–binding protein (SREBP) (Lehmann et al. 2004), (Shultz 2001), CCAAT/enhancer-binding protein-β (CEBPB) (Kuhl, Ross, and Gaido 2007) or NR5A1 (also known as steroidogenic factor 1; Sf1) (Borch et al. 2006). The downstream effects in the pathway might be due to the constellation of earlier events in fetal Leydig cells leading to decrease testosterone production and connected adverse outcomes. Alternative/synergistic MIEs relating to this pathway are hypothesised in the KER description. At present there are no strong views on the other possible MIEs.

Uncertainties, inconsistencies and data gaps

The major uncertainty in this AOP is the functional relationship between (MIE) PPARα activation leading to cholesterol transport reduction; possible mechanisms have been proposed but strong experimental support is missing and some conflicting data are reported. The dose response data to support this relationship are lacking. Studies exploring the role of PPARα using PPARα knockout mice showed that prenatal exposure to phthalates caused developmental malformations in both wild-type and PPARα knockout mice, thus suggesting a PPARα-independent mechanism. However, it is difficult to draw any conclusion on the role of PPARα in phthalate-related reproductive toxicity since the intrauterine administration of phthalate (DEHP) occurred before the critical period of reproductive tract differentiation (Peters et al. 1997). Intrauterine DEHP-treated PPARα-deficient mice, developed delayed testicular, renal and developmental toxicities, but no liver toxicity, compared to wild types, thus confirming the early observation by Lee et al. about the PPARα dependence of liver response and, more importantly, indicating that DEHP may induce reproductive toxicity through both PPARα-dependent and -independent mechanism (Ward et al. 1998). PPARα-independent reproductive toxicity observed by Ward et al. may conceivably be mediated by other PPAR isoforms, such as PPARβ and PPARγ, or by a non-receptor-mediated organ-specific mechanism (Barak et al. 1999). Other studies showed that the administration of DEHP resulted in milder testis lesions and higher testosterone levels in PPARα-null mice than in wild-type mice (Gazouli 2002). A more recent report, investigating the role of PPARα, showed decreased testosterone levels in PPARα(−/−) null control mice, suggesting a positive constitutive role for PPARα in maintaining Leydig cell steroid formation (Borch et al. 2006).

Inconsistencies Genomic studies by Hannas et al., demonstrated that PPARα agonist Wy-14,643, did not reduce foetal testicular testosterone production following gestational day 14–18 exposure, suggesting that the antiandrogenic activity of phthalates is not PPARα mediated (Hannas et al. 2012). Similarly, recent report by Furr et al. did not observe testosterone decrease after administration of Wy-14,643 in rat ( ex vivo) (Furr et al. 2014).

Data Gaps: Complete/pathway driven studies to investigate the effects of PPARs and their role in male reproductive development are lacking. For establishing a solid quantitative and temporal coherent linkage, mode of action framework analysis for PPAR α mediated developmental toxicity are needed. This approach has been applied for the involvement of PPAR α in liver toxicity (Corton et al. 2014), (Wood et al. 2014).

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Empirical information on dose-response relationships between the KEs, are not available, however there are solid empirical data that would inform a computational, predictive model for reproductive toxicity via PPARα activation.

Life Stage Applicability

This AOP is relevant for developing (prenatal) male.

Taxonomic Applicability

The experimental support for the pathway is mainly based on the animal (rat studies). Conflicting reports comes from the studies on mouse. Studies in mice report contradictory results. Recently, studies by Furr et al revealed that fetal T production can be inhibited by exposure to a phthalates in utero (CD-1 mice), but at a higher dose level than required in rats and causing systemic effects (Furr et al. 2014). However there are some earlier reports that chronic dietary administration of phthalates produces adverse testicular effects and reduces fertility in CD-1 mice (Heindel et al. 1989)

Sex Applicability

This AOP applies to males only.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help



Essentiality - KEs

level of confidence


PPAR alpha, Activation

PPAR alpha activation was found to indirectly alter the expression of genes involved in cholesterol transport in mitochondria

very weak

TSPO; StAR decrease

Alterations in the amount of cholesterol transport proteins in mitochondria impact on the levels of substrate for steroid hormones production.


cholesterol transport in mitochondria, reduction

Production of steroid hormones depends on the availability of cholesterol to the enzymes in the mitochondrial matrix. Decreasing the amount of cholesterol inside the mitochondria will result in a diminished amount of substrate for hormone (testosterone) synthesis.


Testosterone synthesis, reduction

The gonads are generally considered the major source of circulating androgens. Consequently, if testosterone synthesis by testes is reduced, testosterone concentrations would be expected to decrease unless there are concurrent reductions in the rate of T catabolism.


Testosterone, reduction

Male sexual differentiation in general depends on androgens (T, dihydrotestosterone (DHT)), disturbances in the balance of this endocrine system by either endogenous or exogenous factors lead to male reproductive tract malformation.


Male reproductive tract malformations

Androgens regulate masculinization of the external genitalia. Therefore any defects in androgen biosynthesis, metabolism or action during foetal development can reproductive tract malformation.


Fertility, impaired

Impaired fertility is the endpoint of reproductive toxicity


Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help



Biological plausibility

Level of confidence

Empirical Support

Level of confidence







PPAR alpha, Activation


Translator protein (TSPO), Decrease

There is functional relationship between PPARα activation and reduction in TSPO levels.

Very Weak

  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose and time point
  • Support for solid temporal relationship is lacking

Very Weak

Some conflicting data

PPAR alpha, Activation


Steroidogenic acute regulatory protein (StAR), decrease

There is functional relationship between PPARα activation and reduction in StAR levels.


  • KEs occur at similar dose levels
  • Support for solid temporal relationship is lacking.


Some conflicting data

Steroidogenic acute regulatory protein (StAR), decrease and Translator protein (TSPO), Decrease


cholesterol transport in mitochondria, reduction

Changes in cholesterol transport proteins can generally be assumed to directly impact levels of cholesterol transport.


  • KEs occur at similar dose levels
  • Support for solid temporal relationship is lacking.


Some conflicting data

cholesterol transport in mitochondria, reduction


testosterone synthesis, reduction

Decreasing the amount of cholesterol inside the mitochondria (e. g by decreasing the expression of enzymes like StAR or TSOP) will result in a diminished amount of substrate for hormone (testosterone) synthesis.


  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose and time point
  • Support for solid temporal relationship is lacking.


Some conflicting data

testosterone, reduction


Male reproductive tract malformations

Reduction in testosterone (T) levels produced in the Leydig cell subsequently lowers the availability of its metabolite; Dihydrotestosterone (DHT).that regulates masculinization of external genitalia. Therefore any defects in androgen biosynthesis, metabolism or action during development can cause male reproductive tract malformation.


  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose and time point
  • Support for solid temporal relationship is lacking.


No conflicting data

Male reproductive tract malformations


Fertility, impaired

Male reproductive tract malformations (congenital malformation of male genitalia) comprise any physical abnormality of the male internal or external genitalia present at birth, which may impair on fertility later in life


  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose and time point

Support for solid temporal relationship is lacking.


No conflicting data

Table 1 Weight of Evidence Summary Table. The underlying questions for the content of the table: Dose-response Does the empirical evidence support that a change in KEup leads to an appropriate change in KEdown?; Does KEup occur at lower doses and earlier time points than KE down and is the incidence of KEup > than that for KEdown?: Incidence Is there higher incidence of KEup than of KEdown?; Inconsistencies/Uncertainties: Are there inconsistencies in empirical support across taxa, species and stressors that don’t align with expected pattern for hypothesized AOP? n.a not applicable

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

This AOP is qualitatively described; however it contains also data that may be used for further development of quantitative description.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

1. The AOP describes a pathway which allows for the detection of sex steroid--related endocrine disrupting modes of action, with focus on the identification of substances which affect the reproductive system. In the current form the pathway lays a strong basis for linking endocrine mode of action with an apical endpoint, a prerequisite requirement for identification of endocrine disrupting chemicals (EDC).

EDCs require specific evaluation under REACH (1907/2006, Registration, Evaluation, Authorisation and Restriction of Chemicals (EU, 2006)), the revised European plant protection product regulation 1107/2009 (EU, 2009) and use of biocidal products 528/2012 EC (EU, 2012).Amongst other agencies the US EPA is also giving particular attention to EDCs (EPA, 1998).

2. This AOP structurally represents current knowledge of the pathway from PPARα activation to impaired fertility that may provide a basis for development (and interpretation) of strategies for Integrated Approaches to Testing Assessment (IATA) to identify similar substances that may operate via the same pathway related tosex steroids disruptionand effects on reproductive tract and fertility. This AOP forms the starting point on an AOP network mapping to modes of action for endocrine disruption.

3. The AOP could inform the development of quantitative structure activity relationships, read-across models, and/or systems biology models to prioritize chemicals for further testing.


List of the literature that was cited for this AOP. 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.

Arlt, W, R J Auchus, and W L Miller. 2001. “Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta -Hydroxysteroid Dehydrogenase.” The Journal of Biological Chemistry 276 (20) (May 18): 16767–71. doi:10.1074/jbc.M100040200.

Barak, Y, M C Nelson, E S Ong, Y Z Jones, P Ruiz-Lozano, K R Chien, A Koder, and R M Evans. 1999. “PPAR Gamma Is Required for Placental, Cardiac, and Adipose Tissue Development.” Molecular Cell 4 (4) (October): 585–95.

Bloomgarden, Z T, W Futterweit, and L Poretsky. 2001. “Use of Insulin-Sensitizing Agents in Patients with Polycystic Ovary Syndrome.” Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 7 (4): 279–86. doi:10.4158/EP.7.4.279.

Boberg, Julie, Stine Metzdorff, Rasmus Wortziger, Marta Axelstad, Leon Brokken, Anne Marie Vinggaard, Majken Dalgaard, and Christine Nellemann. 2008. “Impact of Diisobutyl Phthalate and Other PPAR Agonists on Steroidogenesis and Plasma Insulin and Leptin Levels in Fetal Rats.” Toxicology 250 (2-3) (September 4): 75–81. doi:10.1016/j.tox.2008.05.020.

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.

Corton, J Christopher, Michael L Cunningham, B Timothy Hummer, Christopher Lau, Bette Meek, Jeffrey M Peters, James A Popp, Lorenz Rhomberg, Jennifer Seed, and James E Klaunig. 2014. “Mode of Action Framework Analysis for Receptor-Mediated Toxicity: The Peroxisome Proliferator-Activated Receptor Alpha (PPARα) as a Case Study.” Critical Reviews in Toxicology 44 (1) (January): 1–49. doi:10.3109/10408444.2013.835784.

Corton, J. Christopher, and Paula J Lapinskas. 2004. “Peroxisome Proliferator-Activated Receptors: Mediators of Phthalate Ester-Induced Effects in the Male Reproductive Tract?” Toxicological Sciences 83 (1) (October 13): 4–17. doi:10.1093/toxsci/kfi011.

Couto, Janaína A, Karina L A Saraiva, Cleiton D Barros, Daniel P Udrisar, Christina A Peixoto, Juliany S B César Vieira, Maria C Lima, Suely L Galdino, Ivan R Pitta, and Maria I Wanderley. 2010. “Effect of Chronic Treatment with Rosiglitazone on Leydig Cell Steroidogenesis in Rats: In Vivo and Ex Vivo Studies.” Reproductive Biology and Endocrinology : RB&E 8 (1) (January): 13. doi:10.1186/1477-7827-8-13.

David, RM. 2006. “Proposed Mode of Action for in Utero Effects of Some Phthalate Esters on the Developing Male Reproductive Tract.” Toxicologic Pathology. doi:10.1080/01926230600642625.

Dunaif, A, D Scott, D Finegood, B Quintana, and R Whitcomb. 1996. “The Insulin-Sensitizing Agent Troglitazone Improves Metabolic and Reproductive Abnormalities in the Polycystic Ovary Syndrome.” The Journal of Clinical Endocrinology and Metabolism 81 (9) (September): 3299–306. doi:10.1210/jcem.81.9.8784087.

Ema, Makoto. 2002. “Antiandrogenic Effects of Dibutyl Phthalate and Its Metabolite, Monobutyl Phthalate, in Rats.” Congenital Anomalies 42 (4) (December): 297–308. doi:10.1111/j.1741-4520.2002.tb00896.x.

Furr, Johnathan R, Christy S Lambright, Vickie S Wilson, Paul M Foster, and Leon E Gray. 2014. “A Short-Term in Vivo Screen Using Fetal Testosterone Production, a Key Event in the Phthalate Adverse Outcome Pathway, to Predict Disruption of Sexual Differentiation.” Toxicological Sciences : An Official Journal of the Society of Toxicology 140 (2) (August 1): 403–24. doi:10.1093/toxsci/kfu081.

Gasic, S, Y Bodenburg, M Nagamani, A Green, and R J Urban. 1998. “Troglitazone Inhibits Progesterone Production in Porcine Granulosa Cells.” Endocrinology 139 (12) (December): 4962–6. doi:10.1210/endo.139.12.6385.

Gasic, S, M Nagamani, A Green, and R J Urban. 2001. “Troglitazone Is a Competitive Inhibitor of 3beta-Hydroxysteroid Dehydrogenase Enzyme in the Ovary.” American Journal of Obstetrics and Gynecology 184 (4) (March): 575–9. doi:10.1067/mob.2001.111242.

Gazouli, M. 2002. “Effect of Peroxisome Proliferators on Leydig Cell Peripheral-Type Benzodiazepine Receptor Gene Expression, Hormone-Stimulated Cholesterol Transport, and Steroidogenesis: Role of the Peroxisome Proliferator-Activator Receptor .” Endocrinology 143 (7) (July 1): 2571–2583. doi:10.1210/en.143.7.2571.

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.

Heindel, J J, D K Gulati, R C Mounce, S R Russell, and J C Lamb. 1989. “Reproductive Toxicity of Three Phthalic Acid Esters in a Continuous Breeding Protocol.” Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology 12 (3) (April): 508–18.

Johnson, Kamin J, Nicholas E Heger, and Kim Boekelheide. 2012. “Of Mice and Men (and Rats): Phthalate-Induced Fetal Testis Endocrine Disruption Is Species-Dependent.” Toxicological Sciences : An Official Journal of the Society of Toxicology 129 (2) (October): 235–48. doi:10.1093/toxsci/kfs206.

Kempná, Petra, Gaby Hofer, Primus E Mullis, and Christa E Flück. 2007. “Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2.” Molecular Pharmacology 71 (3) (March): 787–98. doi:10.1124/mol.106.028902.

Kuhl, Adam J, Susan M Ross, and Kevin W Gaido. 2007. “CCAAT/enhancer Binding Protein Beta, but Not Steroidogenic Factor-1, Modulates the Phthalate-Induced Dysregulation of Rat Fetal Testicular Steroidogenesis.” Endocrinology 148 (12) (December): 5851–64. doi:10.1210/en.2007-0930.

Lapinskas, Paula J., Sherri Brown, Lisa M. Leesnitzer, Steven Blanchard, Cyndi Swanson, Russell C. Cattley, and J. Christopher Corton. 2005. “Role of PPARα in Mediating the Effects of Phthalates and Metabolites in the Liver.” Toxicology 207 (1): 149–163.

Latini, Giuseppe, Egeria Scoditti, Alberto Verrotti, Claudio De Felice, and Marika Massaro. 2008. “Peroxisome Proliferator-Activated Receptors as Mediators of Phthalate-Induced Effects in the Male and Female Reproductive Tract: Epidemiological and Experimental Evidence.” PPAR Research 2008 (January): 359267. doi:10.1155/2008/359267.

Lehmann, Kim P, Suzanne Phillips, Madhabananda Sar, Paul M D Foster, and Kevin W Gaido. 2004. “Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-Butyl) Phthalate.” Toxicological Sciences : An Official Journal of the Society of Toxicology 81 (1) (September 1): 60–8. doi:10.1093/toxsci/kfh169.

Minge, Cadence E, Rebecca L Robker, and Robert J Norman. 2008. “PPAR Gamma: Coordinating Metabolic and Immune Contributions to Female Fertility.” PPAR Research 2008 (January): 243791. doi:10.1155/2008/243791.

Mu, Y M, T Yanase, Y Nishi, N Waseda, T Oda, A Tanaka, R Takayanagi, and H Nawata. 2000. “Insulin Sensitizer, Troglitazone, Directly Inhibits Aromatase Activity in Human Ovarian Granulosa Cells.” Biochemical and Biophysical Research Communications 271 (3) (May 19): 710–3. doi:10.1006/bbrc.2000.2701.

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.

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.

Peters, J M, M W Taubeneck, C L Keen, and F J Gonzalez. 1997. “Di(2-Ethylhexyl) Phthalate Induces a Functional Zinc Deficiency during Pregnancy and Teratogenesis That Is Independent of Peroxisome Proliferator-Activated Receptor-Alpha.” Teratology 56 (5) (November): 311–6. doi:10.1002/(SICI)1096-9926(199711)56:5<311::AID-TERA4>3.0.CO;2-#.

Shipley, Jonathan M, and David J Waxman. 2004. “Simultaneous, Bidirectional Inhibitory Crosstalk between PPAR and STAT5b.” Toxicology and Applied Pharmacology 199 (3) (October 15): 275–84. doi:10.1016/j.taap.2003.12.020.

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.

Thompson, Christopher J, Susan M Ross, Janan Hensley, Kejun Liu, Susanna C Heinze, S Stanley Young, and Kevin W Gaido. 2005. “Differential Steroidogenic Gene Expression in the Fetal Adrenal Gland versus the Testis and Rapid and Dynamic Response of the Fetal Testis to Di(n-Butyl) Phthalate.” Biology of Reproduction 73 (5) (November): 908–17. doi:10.1095/biolreprod.105.042382.

Veldhuis, Johannes D, George Zhang, and James C Garmey. 2002. “Troglitazone, an Insulin-Sensitizing Thiazolidinedione, Represses Combined Stimulation by LH and Insulin of de Novo Androgen Biosynthesis by Thecal Cells in Vitro.” The Journal of Clinical Endocrinology and Metabolism 87 (3) (March): 1129–33. doi:10.1210/jcem.87.3.8308.

Vierhapper, H, P Nowotny, and W Waldhäusl. 2003. “Reduced Production Rates of Testosterone and Dihydrotestosterone in Healthy Men Treated with Rosiglitazone.” Metabolism: Clinical and Experimental 52 (2) (February): 230–2. doi:10.1053/meta.2003.50028.

Ward, J M, J M Peters, C M Perella, and F J Gonzalez. 1998. “Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of di(2-Ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptor Alpha-Null Mice.” Toxicologic Pathology 26 (2): 240–6.

Welsh, Michelle, Philippa T K Saunders, Mark Fisken, Hayley M Scott, Gary R Hutchison, Lee B Smith, and Richard M Sharpe. 2008. “Identification in Rats of a Programming Window for Reproductive Tract Masculinization, Disruption of Which Leads to Hypospadias and Cryptorchidism.” The Journal of Clinical Investigation 118 (4) (April): 1479–90. doi:10.1172/JCI34241.

Wood, Charles E, Micheal P Jokinen, Crystal L Johnson, Greg R Olson, Susan Hester, Michael George, Brian N Chorley, et al. 2014. “Comparative Time Course Profiles of Phthalate Stereoisomers in Mice.” Toxicological Sciences : An Official Journal of the Society of Toxicology 139 (1) (May): 21–34. doi:10.1093/toxsci/kfu025.