To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:608

Relationship: 608

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Reduction, testosterone level leads to Malformation, Male reproductive tract

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
PPARα activation in utero leading to impaired fertility in males non-adjacent High Arthur Author (send email) Open for citation & comment EAGMST Under Review

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mice Mus sp. Low NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

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).

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

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).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

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).

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

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

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

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.

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. http://www.ncbi.nlm.nih.gov/pubmed/12773767.

Brouwers, Marijn M, Wouter F J Feitz, Luc A J Roelofs, Lambertus A L M Kiemeney, Robert P E de Gier, and Nel Roeleveld. 2007. “Risk Factors for Hypospadias.” European Journal of Pediatrics 166 (7) (July): 671–8. doi:10.1007/s00431-006-0304-z. http://www.ncbi.nlm.nih.gov/pubmed/17103190.

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.

Eisenberg, Michael L, Tina K Jensen, R Chanc Walters, Niels E Skakkebaek, and Larry I Lipshultz. 2011. “The Relationship between Anogenital Distance and Reproductive Hormone Levels in Adult Men.” The Journal of Urology 187 (2) (February): 594–8. doi:10.1016/j.juro.2011.10.041. http://www.ncbi.nlm.nih.gov/pubmed/22177168.

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.

Johnson, Kamin J, Erin N McDowell, Megan P Viereck, and Jessie Q Xia. 2011. “Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways.” Toxicological Sciences : An Official Journal of the Society of Toxicology 120 (2) (April): 460–74. doi:10.1093/toxsci/kfr020. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3061485&tool=pmcentrez&rendertype=abstract.

Jurewicz, Joanna, and Wojciech Hanke. 2011. “Exposure to Phthalates: Reproductive Outcome and Children Health. A Review of Epidemiological Studies.” International Journal of Occupational Medicine and Environmental Health 24 (2) (June): 115–41. doi:10.2478/s13382-011-0022-2. http://www.ncbi.nlm.nih.gov/pubmed/21594692. 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. http://www.ncbi.nlm.nih.gov/pubmed/18637150.

Klip, Helen, Janneke Verloop, Jan D van Gool, Marlies E T A Koster, Curt W Burger, and Flora E van Leeuwen. 2002. “Hypospadias in Sons of Women Exposed to Diethylstilbestrol in Utero: A Cohort Study.” Lancet 359 (9312) (March 30): 1102–7. doi:10.1016/S0140-6736(02)08152-7. http://www.ncbi.nlm.nih.gov/pubmed/11943257.

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. http://www.ncbi.nlm.nih.gov/pubmed/20002220. 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. http://www.ncbi.nlm.nih.gov/pubmed/14745936.

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. http://www.ncbi.nlm.nih.gov/pubmed/11452136.

McIntyre, B S, N J Barlow, D G Wallace, S C Maness, K W Gaido, and P M Foster. 2000. “Effects of in Utero Exposure to Linuron on Androgen-Dependent Reproductive Development in the Male Crl:CD(SD)BR Rat.” Toxicology and Applied Pharmacology 167 (2) (September 1): 87–99. doi:10.1006/taap.2000.8998. http://www.ncbi.nlm.nih.gov/pubmed/10964759.

Moore, R W, T A Rudy, T M Lin, K Ko, and R E Peterson. 2001. “Abnormalities of Sexual Development in Male Rats with in Utero and Lactational Exposure to the Antiandrogenic Plasticizer Di(2-Ethylhexyl) Phthalate.” Environmental Health Perspectives 109 (3) (March): 229–37. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1240240&tool=pmcentrez&rendertype=abstract.

Morales-Suárez-Varela, María M, Gunnar V Toft, Morten S Jensen, Cecilia Ramlau-Hansen, Linda Kaerlev, Ane-Marie Thulstrup, Agustín Llopis-González, Jørn Olsen, and Jens P Bonde. 2011. “Parental Occupational Exposure to Endocrine Disrupting Chemicals and Male Genital Malformations: A Study in the Danish National Birth Cohort Study.” Environmental Health : A Global Access Science Source 10 (1) (January): 3. doi:10.1186/1476-069X-10-3. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3033238&tool=pmcentrez&rendertype=abstract.

Murashima, Aki, Satoshi Kishigami, Axel Thomson, and Gen Yamada. 2015. “Androgens and Mammalian Male Reproductive Tract Development.” Biochimica et Biophysica Acta 1849 (2) (February): 163–170. doi:10.1016/j.bbagrm.2014.05.020. http://www.sciencedirect.com/science/article/pii/S1874939914001266.

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. http://www.toxsci.oupjournals.org/cgi/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. http://toxsci.oxfordjournals.org/content/43/1/47.short?rss=1&ssource=mfc.

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. http://toxsci.oxfordjournals.org/content/58/2/339.abstract.

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. http://www.ncbi.nlm.nih.gov/pubmed/16131574.

Saillenfait, Anne-Marie, Frédéric Gallissot, and Jean-Philippe Sabaté. 2009. “Differential Developmental Toxicities of Di-N-Hexyl Phthalate and Dicyclohexyl Phthalate Administered Orally to Rats.” Journal of Applied Toxicology : JAT 29 (6) (August): 510–21. doi:10.1002/jat.1436. http://www.ncbi.nlm.nih.gov/pubmed/19391110.

Suzuki, Y, J Yoshinaga, Y Mizumoto, S Serizawa, and H Shiraishi. 2012. “Foetal Exposure to Phthalate Esters and Anogenital Distance in Male Newborns.” International Journal of Andrology 35 (3) (June): 236–44. doi:10.1111/j.1365-2605.2011.01190.x. http://www.ncbi.nlm.nih.gov/pubmed/21696396.

Swan, S. H., S. Sathyanarayana, E. S. Barrett, S. Janssen, F. Liu, R. H. N. Nguyen, and J. B. Redmon. 2015. “First Trimester Phthalate Exposure and Anogenital Distance in Newborns.” Human Reproduction 30 (4) (February 18): 963–72. doi:10.1093/humrep/deu363. http://www.ncbi.nlm.nih.gov/pubmed/25697839.

Swan, Shanna H, Katharina M Main, Fan Liu, Sara L Stewart, Robin L Kruse, Antonia M Calafat, Catherine S Mao, et al. 2005. “Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure.” Environmental Health Perspectives 113 (8) (August): 1056–61. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1280349&tool=pmcentrez&rendertype=abstract.

Virtanen, Helena E, Dina Cortes, Ewa Rajpert-De Meyts, E Martin Ritzén, Agneta Nordenskjöld, Niels E Skakkebaek, and Jorma Toppari. 2007. “Development and Descent of the Testis in Relation to Cryptorchidism.” Acta Paediatrica (Oslo, Norway : 1992) 96 (5) (May): 622–7. doi:10.1111/j.1651-2227.2007.00244.x. http://www.ncbi.nlm.nih.gov/pubmed/17462055.

Wang, Ming-Hsien, and Laurence S Baskin. 2008. “Endocrine Disruptors, Genital Development, and Hypospadias.” Journal of Andrology 29 (5): 499–505. doi:10.2164/jandrol.108.004945. http://www.ncbi.nlm.nih.gov/pubmed/18497336.

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.