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Event: 348

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Malformation, Male reproductive tract

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Malformation, Male reproductive tract

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
male reproductive system

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
male reproductive organ morphological change

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
PPARα activation leading to impaired fertility AdverseOutcome Elise Grignard (send email) Open for citation & comment EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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 in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Biological state

Male reproductive tract malformations (congenital malformation of male genitalia) comprise any physical abnormality of the male internal or external genitalia present at birth. Some result from excessive or deficient androgen effect, others result from teratogenic effects, or are associated with anomalies of other parts of the body in a recognizable pattern (i.e., a syndrome). The cause of many of these birth defects is unknown.

Hypospadias is a defect of the urogenital system, a malformation in which the urethra opens on the underside of the penis instead of the tip. It results from an incomplete closure of the urethral folds, leaving a split on the penis (Kalfa, Philibert, and Sultan 2009). When the urethra opens to the glans or corona of the penis, it is called distal, whereas opening to the shaft or penoscrotal area defines hypospadias as proximal. Androgens regulate the masculinization of external genitalia. Therefore any defects in androgen biosynthesis, metabolism or action during foetal development can cause hypospadias. Gene defects causing disorders of testicular differentiation, conversion of testosterone to dihydrotestosterone or mutations in the androgen receptor can also result in hypospadias (Kalfa et al. 2008). In about 20% of patients with isolated hypospadias there are signs of endocrine abnormalities by the time of diagnosis (Rey et al. 2005). The majority of hypospadias are believed to have a multifactorial etiology, although a small percentage do result from single gene mutations (Baskin, Himes, and Colborn 2001). The only treatment of hypospadias is surgery, thus, prevention is imperative.

Biological compartments: reproductive system

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Malformations are detected by macroscopically for any structural abnormality or pathological change. The Congenital malformation of the genitalia is a medical term referring to a broad category of conditions that for humans is classified by International Classification of Diseases (ICD) in chapter "Congenital malformations of genital organs" (Q50-Q56) e.g.Q54 Hypospadias, Q53 Undescended testicle. Hypospadias is usually diagnosed during the routine examination after birth. The hypospadias belongs to the category of "Congenital malformation of the genitalia" - a medical term referring to a broad category of conditions as classified in the International Classification of Diseases (ICD) in chapter "Congenital malformations of genital organs" (Q50-Q56) e.g. Q54 Hypospadias.

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, the distance from the anus to the genitals, is widely used as biomarker of prenatal androgen exposure during a reproductive programming window (Wolf et al. 1999), (McIntyre, Barlow, and Foster 2001), (Macleod et al. 2010). 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). Measurement of AGD has also been proposed as a quantitative biomarker of foetal endocrine disruptor exposure in humans (Arbuckle et al. 2008), (Dean and Sharpe 2013). A longer (more “masculine”) AGD is typically associated with favourable health outcomes, while a shorter AGD is associated with adverse health outcomes. The AGD in males is approximately double that of females. Less is known about clinical correlates of AGD in females, although one study found that in women a longer AGD was associated with increased odds of multifollicular ovaries (Mendiola et al. 2012). The AGD is reflecting the prenatal hormonal milieu and in addition a biomarker for the risk of reproductive health problems linked to that early hormonal environment (Barrett et al. 2014). In animal studies, AGD measured from the genital tubercle to the anus is a sensitive marker of in utero exposure to androgens and anti-androgens, and is used extensively in animal reproductive toxicology studies (McIntyre, Barlow, and Foster 2001). AGD of each pup should be measured on at least one occasion from pre natal day postnatal day (PND) 0 through PND 4. Pup body weight should be collected on the day the AGD is measured and the AGD should be normalized to a measure of pup size, preferably the cube root of body weight (12). AGD is influenced by the body weight of the animal and therefore, this should be taken into account when evaluating the data (Gallavan et al, 1999). Body weight as a covariable may also be used (Howdeshell et al. 2007). Decreased AGD in male rats is a hallmark of exposure to antiandrogenic substances (Noriega et al, 2009; Christiansen et al, 2010). A statistically significant change in AGD that cannot be explained by the size of the animal indicates an adverse effect of exposure and should be considered in setting the NOAEL (OECD, 2008).

The extended one-generation in vivo reproductive toxicity study OECD TG 443 [1]is used to investigate adverse effects of chemical substances on fertility and developmental toxicity in the rat, in which AGD is measured.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Hypospadias

Rodents (Gray et al. 2001) Human (Manson and Carr 2003) Wildlife species (Hayes et al. 2002)

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

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

In regulatory hazard identification and risk assessment of chemicals malformations of male genitalia are considered as a chemically induced adverse outcome that is used for risk assessment and management purposes. The prenatal developmental toxicity study (TG 414) is the method for examining embryo-foetal toxicity as a consequence of exposure during pregnancy. Parental and offspring growth, development and viability are the relevant endpoints in generation studies (OECD TG 415/416/443). These guidelines are implemented in a number of occasions where the reproductive /developmental toxicity have to be assessed in order to comply with relevant EU regulations.

Under REACH, information on reproductive toxicity is required for chemicals with an annual production/importation volume of 10 metric tonnes or more. Standard information requirements include a screening study on reproduction toxicity (OECD TG 421/422) at Annex VIII (10-100 t.p.a), a prenatal developmental toxicity study (OECD 414) on a first species at Annex IX (100-1000 t.p.a), and from March 2015 the OECD 443(Extended One-Generation Reproductive Toxicity Study) is reproductive toxicity requirement instead of the two generation reproductive toxicity study (OECD TG 416). If not conducted already at Annex IX, a prenatal developmental toxicity study on a second species at Annex X (≥ 1000 t.p.a.).

Under the Biocidal Products Regulation (BPR), information is also required on reproductive toxicity for active substances as part of core data set and additional data set (EU 2012, ECHA 2013). As a core data set, prenatal developmental toxicity study (EU TM B.31) in rabbits as a first species and a two-generation reproduction toxicity study (EU TM B.31) are required. OECD TG 443 (Extended One-Generation Reproductive Toxicity Study) shall be considered as an alternative approach to the multi-generation study.

According to the Classification, Labelling and Packaging (CLP) regulation (EC, 200; Annex I: 3.7.1.1): a) “reproductive toxicity” includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring; b) “effects on fertility” includes adverse effects on sexual function and fertility; and c) “developmental toxicity” includes adverse effects on development of the offspring.

AGD is a reproductive endpoint, assessment of AGD is mandatory in OECD TG 443, 415/416 (OECD 2012).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Arbuckle, Tye E, Russ Hauser, Shanna H Swan, Catherine S Mao, Matthew P Longnecker, Katharina M Main, Robin M Whyatt, et al. 2008. “Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life.” Environmental Health Perspectives 116 (7) (July): 948–51. doi:10.1289/ehp.11226.

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.

Baskin, L S, K Himes, and T Colborn. 2001. “Hypospadias and Endocrine Disruption: Is There a Connection?” Environmental Health Perspectives 109 (11) (November): 1175–83.

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.

Dean, Afshan, and Richard M Sharpe. 2013. “Clinical Review: Anogenital Distance or Digit Length Ratio as Measures of Fetal Androgen Exposure: Relationship to Male Reproductive Development and Its Disorders.” The Journal of Clinical Endocrinology and Metabolism 98 (6) (June): 2230–8. doi:10.1210/jc.2012-4057.

Gray, L E, J Ostby, J Furr, C J Wolf, C Lambright, L Parks, D N Veeramachaneni, et al. 2001. “Effects of Environmental Antiandrogens on Reproductive Development in Experimental Animals.” Human Reproduction Update 7 (3): 248–64.

Hayes, Tyrone B, Atif Collins, Melissa Lee, Magdelena Mendoza, Nigel Noriega, A Ali Stuart, and Aaron Vonk. 2002. “Hermaphroditic, Demasculinized Frogs after Exposure to the Herbicide Atrazine at Low Ecologically Relevant Doses.” Proceedings of the National Academy of Sciences of the United States of America 99 (8) (April 16): 5476–80. doi:10.1073/pnas.082121499.

Howdeshell, Kembra L, Johnathan Furr, Christy R Lambright, Cynthia V Rider, Vickie S Wilson, and L Earl Gray. 2007. “Cumulative Effects of Dibutyl Phthalate and Diethylhexyl Phthalate on Male Rat Reproductive Tract Development: Altered Fetal Steroid Hormones and Genes.” Toxicological Sciences : An Official Journal of the Society of Toxicology 99 (1) (September): 190–202. doi:10.1093/toxsci/kfm069.

Kalfa, Nicolas, Benchun Liu, Ophir Klein, Ming-Hsieh Wang, Mei Cao, and Laurence S Baskin. 2008. “Genomic Variants of ATF3 in Patients with Hypospadias.” The Journal of Urology 180 (5) (November): 2183–8; discussion 2188. doi:10.1016/j.juro.2008.07.066.

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.

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.

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.

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.

Mendiola, Jaime, Manuela Roca, Lidia Mínguez-Alarcón, Maria-Pilar Mira-Escolano, José J López-Espín, Emily S Barrett, Shanna H Swan, and Alberto M Torres-Cantero. 2012. “Anogenital Distance Is Related to Ovarian Follicular Number in Young Spanish Women: A Cross-Sectional Study.” Environmental Health : A Global Access Science Source 11 (January): 90. doi:10.1186/1476-069X-11-90.

OECD. 2012. Test No. 443: Extended One-Generation Reproductive Toxicity Study. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing. doi:10.1787/9789264185371-en.

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.

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.