Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII)

13311-84-7

MKXKFYHWDHIYRV-UHFFFAOYSA-N

Flutamide

Propanamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]- 4-Nitro-3-(trifluoromethyl)isobutyranilide 4'-Nitro-3'-trifluoromethylisobutyranilide Eulexin Flucinom Flutamid flutamida m-Propionotoluidide, α,α,α-trifluoro-2-methyl-4'-nitro- N-(Isopropylcarbonyl)-4-nitro-3-trifluoromethylaniline Niftholide Niftolide NSC 147834 NSC 215876

DTXSID7032004

50471-44-8

FSCWZHGZWWDELK-UHFFFAOYNA-N

FSCWZHGZWWDELK-UHFFFAOYSA-N

Vinclozolin

2,4-Oxazolidinedione, 3-(3,5-dichlorophenyl)-5-ethenyl-5-methyl- (.+-.)-Vinclozolin BAS 352-04F N-3,5-Dichlorophenyl-5-methyl-5-vinyl-1,3-oxazolidine-2,4-dione N-3,5-Dichlorophenyl-5-methyl-5-vinyloxazolidine-2,4-dione N-3,5-Dichlorphenyl-5-methyl-5-vinyl-1,3-oxazolidin-2,4-dion N-3,5-diclorofenil-5-metil-5-vinil-1,3-oxazolidina-2,4-diona Ornalin Ranilan Ronilan Ronilan 50WP

DTXSID4022361

117-81-7

BJQHLKABXJIVAM-UHFFFAOYNA-N

BJQHLKABXJIVAM-UHFFFAOYSA-N

Di(2-ethylhexyl) phthalate

1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester DEHP 1,2-Benzedicarboxylic acid, bis(2-ethyl-hexyl) ester 1,2-Benzenedicarboxylic acid bis(2-ethylhexyl) ester 1,2-Benzenedicarboxylic acid, 1,2-bis(2-ethylhexyl) ester 1,2-Benzenedicarboxylic acid,bis(2-ethylhexylester) Bis(2-ethylhexyl) 1,2-benzenedicarboxylate Bis(2-ethylhexyl) o-phthalate bis(2-ethylhexyl) phthalate Bis(2-ethylhexyl)phthalat Bis(2-ethylhexyl)phthalate Bisoflex 81 Bisoflex DOP Corflex 400 Di(2-ethylhexyl)phthalate Di(isooctyl) phthalate Di-2-ethylhexlphthalate Di-2-ethylhexyl phthalate DI-2-ETHYLHEXYL-PHTHALATE Diacizer DOP Diethylhexyl phthalate Dioctylphthalate DOF Ergoplast FDO Ergoplast FDO-S ETHYLHEXYL PHTHALATE Eviplast 80 Eviplast 81 Fleximel Flexol DOD Flexol DOP ftlalato de bis(2-etilhexilo) Garbeflex DOP-D 40 Good-rite GP 264 Hatco DOP Jayflex DOP Kodaflex DEHP Kodaflex DOP Monocizer DOP NSC 17069 Palatinol AH Palatinol AH-L Phtalate de Bis (Ethyle-2-Hexyle) Phtalate de bis(2-ethylhexyle) PHTHALATE, BIS(2-ETHYLHEXYL) Phthalic acid di(2-ethylhexyl) ester Phthalic acid, bis(2-ethylhexyl) ester PHTHALIC ACID, BIS(2-ETHYLHEXYL)ESTER PHTHALSAEURE-BIS-(2-AETHYLHEXYL)-ESTER Pittsburgh PX 138 Plasthall DOP Reomol D 79P Sansocizer DOP Sansocizer R 8000 Sconamoll DOP Staflex DOP Truflex DOP Vestinol AH Vinycizer 80 Vinycizer 80K Witcizer 312

DTXSID5020607

PR:000011405

PR COUP transcription factor 2

CHEBI:17347

CHEBI testosterone

UBERON:0001301

UBERON epididymis

FMA:67338

FMA Mature sperm cell

GO:0035624

GO receptor transactivation

GO:0050810

GO regulation of steroid biosynthetic process

GO:0042446

GO hormone biosynthetic process

GO:0061370

GO testosterone biosynthetic process

GO:0048645

GO animal organ formation

HP:0008669

HP Abnormal spermatogenesis

WIKI decreased

WIKI abnormal

Flutamide

2016-11-29T18:42:27

Vinclozolin

2020-05-14T11:28:31

Bis(2-ethylhexyl) phthalate

2016-11-29T18:42:08

WikiUser_17

mammals

WikiUser_28

Vertebrates

Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII)

Decreased COUP-TFII in Leydig cells

Cellular

Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII), also known as Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) (Mendoza-Villarroel et al. 2014), is a nuclear receptor involved in various metabolic systems including lipid regulation and steroid synthesis (Qin et al. 2008; van den Driesche et al. 2012; Ashraf et al. 2018).   COUP-TFII has been shown to interact with Retinoid X Receptor (RXR) and Glucocorticoid Receptor (GR) (Ashraf et al. 2018).  Decrease in COUP-TFII expression has been linked to metabolic and developmental disorders.

COUP-TFII is measured by changes in gene expression and protein levels.  Effects of COUP-TFII on expression of downstream genes can be investigating using metabolomics and RT-qPCR approaches.  In addition, targeted ToxCast assays using SeqAPASS evaluations can evaluate gene expression changes from chemical exposure for model species (NCBI Accession Number NP_066285.1 for NR2F2 in Lalone et al. 2018).

Life Stage: Applies to all life stages. Sex: Applies to both males and females. Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.

CL:0000255

CL eukaryotic cell

Moderate Unspecific

High

Development

Moderate

Ashraf, U.M., Sanchez, E.R., and Kumarasamy, S.  2019.  COUP-TFII Revisited: Its Role in Metabolic Gene Regulation.  Steroids 141: 63–69. LaLone, C.A., Villeneuve, D.L., Doering, J.A., Blackwell, B.R., Transue, T.R., Simmons, C.W., Swintek, J., Degitz, S.J., Williams, A.J., and Ankley, G.T.  2018.  Evidence for Cross Species Extrapolation of Mammalian-Based High-Throughput Screening Assay Results.  Environmental Science and Technology 52: 13960−13971. Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064.   NOTE: Italics symbolize edits from John Frisch     AOPWiki 2016-11-29T18:41:26

2024-04-16T09:08:50

Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells

Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes

Cellular

Steroids are hormones that play important roles in reproductive development and function.  Multiple pathways control the rate of steroidogenesis ensuring that proper steroid levels are present during development.  Decreased steroidogenesis rates of androgens has been linked to malformation of reproductive organs and decreased reproduction function (see Palermo et al. 2021 for review with focus on exposure to phthalates).  Efforts have been made to isolate when steroidogenesis rates and resulting steroid levels are most critical for proper reproductive development in lab mammals by targeted disruption by toxicants during different periods of development (Foster and Harris 2005; Welsh 2008).

Rates of steroidogenesis are measured by changes in gene expression and protein levels.  Gene/protein families with known effects on regulation (ex. STAR steroidogenic acute regulatory protein (STaR)) or production of androgens (ex. Cytochrome P450 11 (CYP11); Cytochrome P450 17 (CYP17); 3β-Hydroxysteroid dehydrogenase (3 β-HSD)) are typically studied (Qin et al. 2008; van den Driesche et al. 2012; Mendoza-Villarroel et al. 2014).  Effects on expression of downstream genes can be investigating using metabolomics and RT-qPCR approaches, as well as measuring steroid levels (often testosterone).  In addition, targeted ToxCast assays using SeqAPASS evaluations can evaluate gene expression changes from chemical exposure for model species (HT-H295R assay in Lalone et al. 2018).

CL:0000255

CL eukaryotic cell

Moderate Unspecific

High

Development

Moderate

Foster, P.M.D. and Harris, M.W.  2005.  Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages.  Toxicological Sciences 85: 1024–1032. LaLone, C.A., Villeneuve, D.L., Doering, J.A., Blackwell, B.R., Transue, T.R., Simmons, C.W., Swintek, J., Degitz, S.J., Williams, A.J., and Ankley, G.T.  2018.  Evidence for Cross Species Extrapolation of Mammalian-Based High-Throughput Screening Assay Results.  Environmental Science and Technology 52: 13960−13971. Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064. Welsh, M., Saunders, P.T.K., Fisken, M., Scott, H.M., Hutchison, G.R., Smith, L.R. and Sharpe, R.M.  2008.  Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.  Journal of Clinical Investigation 118(4): 1479-1490. NOTE: Italics symbolize edits from John Frisch     AOPWiki 2016-11-29T18:41:26

2024-04-16T10:07:31

Decrease, testosterone levels

Tissue

Testosterone is an endogenous steroid hormone and a potent androgen. Androgens act by binding androgen receptors in androgen-responsive tissues (Murashima et al., 2015). Testosterone and other androgens such as dihydrotestosterone (DHT) are important for reproductive development and masculinization of the fetus. Androgens are also important for bone, brain, muscle and skin health (Alemany, 2022). Just like other steroid hormones, testosterone is produced through a process known as steroidogenesis which is controlled by enzymes converting cholesterol into all of the downstream steroid hormones. In steroidogenesis, androstenedione or androstenediol is converted to testosterone by the enzymes 17β-hydroxysteroid dehydrogenase (HSD) or 3β-HSD, respectively. Testosterone can then be converted to the more potent androgen, DHT, by 5α-reductase, or aromatized by aromatase (CYP19A1) into estrogens. Testosterone secreted in blood circulation can be found free but more frequently is found bound to SHBG or albumin (Trost & Mulhall, 2016). Testosterone is produced mainly by the ovaries (in females ), testes (in males), and to  a lesser degree in the adrenal glands. During fetal development testosterone plays a crucial role in the differentiation of male reproductive tissues and the overall male phenotype. In adulthood, testosterone synthesis is controlled by the Hypothalamus-Pituitary-Gonadal (HPG) axis. GnRH is released from the hypothalamus inducing LH pulses secreted by the anterior pituitary. This LH surge leads to increased testosterone production. If testosterone reaches low levels, this axis is once again stimulated to provoke more testosterone synthesis. This feedback loop is essential for maintenance of appropriate testosterone levels (Chandrashekar & Bartke, 1998; Ellis et al., 1983; Rey, 2021). Disruption of any of the aforementioned processes may result in reduced testosterone levels, such as inhibition of steroidogenic enzyme activity thereby inhibiting production of testosterone. General role in biology Androgens, the main male sex steroids, are the critical factors responsible for the development of the male phenotype during embryogenesis and for the achievement of sexual maturation at puberty. In adulthood, androgens remain essential for the maintenance of male reproductive function and behaviour. Apart from their effects on reproduction, androgens affect a wide variety of non-reproductive tissues such as skin, bone, muscle, and brain (Heemers, Verhoeven, & Swinnen, 2006). Androgens, principally T and 5α-dihydrotestosterone (DHT), exert most of their effects by interacting with a specific receptor, the androgen receptor (AR), for review see (Murashima, Kishigami, Thomson, & Yamada, 2015). On the one hand, testosterone can be reduced by 5α-reductase to produce 5α dihydrotestosterone (DHT). On the other hand, testosterone can be aromatized to generate estrogens. Testosterone effects can also be classified by the age of usual occurrence, postnatal effects in both males and females are mostly dependent on the levels and duration of circulating free testosterone.

Quantification of testosterone levels can be performed by various means (e.g. serum levels in vivo, cell culture medium levels in vitro, tissue ex vivo or in vitro). Traditional immunoassay methods (ELISA or RIA), and advanced instrumental techniques (e.g. LC-MS/MS) or liquid scintillation spectrometry (after radiolabeling) can be used (Shiraishi et al., 2008). The H295R Steroidogenesis assay (OECD TG 456) is used to measure mainly the production of estradiol and testosterone. This is a validated OECD test guideline using adrenal H295R cells and hormone levels are then measured in the cell medium (OECD 2011). H295R adrenocortical carcinoma cells produce all the main enzymes and hormones of the steroidogenic pathway. Therefore, exposure to different stressors allows for broad analysis of their impact on steroidogenesis by measuring hormones in culture medium by LC-MS/MS. H295 assay was designed measure disruption to testosterone or estradiol levels but can now also be used to measure additional steroid hormones such as progesterone or pregnenolone. The U.S. EPA’s ToxCast program developed a high throughput method for the H295R assay which can measure a total of 11 hormones from the steroidogenesis pathway (Haggard et al., 2018). The H295R can be considered an indirect measurement as it provides information on a disruption of overall steroidogenesis that would result in a change of testosterone levels but not the underlying mechanism. Testosterone can be measured by immunoassays and by isotope-dilution gas chromatography-mass spectrometry in serum (Taieb et al., 2003), (Paduch et al., 2014). Testosterone levels are measured i.a. in: Fish Lifecycle Toxicity Test (FLCTT) (US EPA OPPTS 850.1500), Male pubertal assay (PP Male Assay) (US EPA OPPTS 890.1500), OECD TG 441: Hershberger Bioassay in Rats (H Assay).

This KE is applicable to mammals since the role of testosterone and its synthesis are conserved (Vitousek et al., 2018). Both sexes need, and produce, testosterone and its role is observed throughout different life stages, from development to adulthood (Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022). Therefore, this KE is also applicable to both males and females as well as throughout these life stages. Also of note, key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, it is acknowledged that this KE most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability beyond mammals to other vertebrates. Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.

UBERON:0000178

UBERON blood

High Mixed

High

During development and at adulthood

High

Alemany, M. (2022). The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health. International Journal of Molecular Sciences, 23(19), 11952. https://doi.org/10.3390/ijms231911952 Baker, M.E. (2011). Insights from the structure of estrogen receptor into the evolution of estrogens: implications for endocrine disruption. Biochem Pharmacol, 82(1), 1-8. <a href="https://doi.org/10.1016/j.bcp.2011.03.008" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.bcp.2011.03.008</a> Chandrashekar, V., & Bartke, A. (1998). The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats*. Endocrinology, 139(3), 1067–1074. https://doi.org/10.1210/endo.139.3.5816 Ellis, G. B., Desjardins, C., & Fraser, H. M. (1983). Control of Pulsatile LH Release in Male Rats. Neuroendocrinology, 37(3), 177–183. https://doi.org/10.1159/000123540 Haggard, D. E., Karmaus, A. L., Martin, M. T., Judson, R. S., Setzer, R. W., & Paul Friedman, K. (2018). High-Throughput H295R Steroidogenesis Assay: Utility as an Alternative and a Statistical Approach to Characterize Effects on Steroidogenesis. Toxicological Sciences, 162(2), 509–534. https://doi.org/10.1093/toxsci/kfx274 Heemers, H. V, Verhoeven, G., & Swinnen, J. V. (2006). Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. Molecular Endocrinology (Baltimore, Md.), 20(10), 2265–77. doi:10.1210/me.2005-0479 Luetjens, C. M., & Weinbauer, G. F. (2012). Testosterone: biosynthesis, transport, metabolism and (non-genomic) actions. In Testosterone (pp. 15–32). Cambridge University Press. https://doi.org/10.1017/CBO9781139003353.003 Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1849(2), 163–170. https://doi.org/10.1016/j.bbagrm.2014.05.020 Naamneh Elzenaty, R., du Toit, T., & Flück, C. E. (2022). Basics of androgen synthesis and action. Best Practice & Research Clinical Endocrinology & Metabolism, 36(4), 101665. https://doi.org/10.1016/j.beem.2022.101665 Paduch, D. A., Brannigan, R. E., Fuchs, E. F., Kim, E. D., Marmar, J. L., & Sandlow, J. I. (2014). The laboratory diagnosis of testosterone deficiency. Urology, 83(5), 980–8. doi:10.1016/j.urology.2013.12.024 Rey, R. A. (2021). The Role of Androgen Signaling in Male Sexual Development at Puberty. Endocrinology, 162(2). https://doi.org/10.1210/endocr/bqaa215 Shiraishi, S., Lee, P. W. N., Leung, A., Goh, V. H. H., Swerdloff, R. S., & Wang, C. (2008). Simultaneous Measurement of Serum Testosterone and Dihydrotestosterone by Liquid Chromatography–Tandem Mass Spectrometry. Clinical Chemistry, 54(11), 1855–1863. https://doi.org/10.1373/clinchem.2008.103846 Taieb, J., Mathian, B., Millot, F., Patricot, M.-C., Mathieu, E., Queyrel, N., … Boudou, P. (2003). Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clinical Chemistry, 49(8), 1381–95. Trost, L. W., & Mulhall, J. P. (2016). Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials. The Journal of Sexual Medicine, 13(7), 1029–1046. https://doi.org/10.1016/j.jsxm.2016.04.068 Vitousek, M. N., Johnson, M. A., Donald, J. W., Francis, C. D., Fuxjager, M. J., Goymann, W., Hau, M., Husak, J. F., Kircher, B. K., Knapp, R., Martin, L. B., Miller, E. T., Schoenle, L. A., Uehling, J. J., & Williams, T. D. (2018). HormoneBase, a population-level database of steroid hormone levels across vertebrates. Scientific Data, 5(1), 180097. https://doi.org/10.1038/sdata.2018.97 AOPWiki 2019-08-30T04:40:53

2024-05-24T12:27:55

Epididymal agenesis

Organ

Epididymal agenesis and abnormal epididymal organ formation are indicative of improper reproductive organ formation during development, which can impact proper reproductive function (see Palermo et al. 2021 for review with focus on exposure to phthalates).  Research in laboratory mammals has focused on the levels of steroid compounds necessary for proper reproductive development (Wilson et al. 2007; Kim et al. 2010; Gray et al. 2016), and the targeted disruption by toxicants during different periods of development (Foster and Harris 2005; Welsh et al. 2008).

Histological observations are required to detect failure for the epididymis to develop, as well as other abnormalities with the epididymis and surrounding reproductive tissue.  Lower organ weight is suggestive that problems may be present but not a substitute for histological examination.

Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals. Sex: Applies to both males and females. Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.

UBERON:0001301

UBERON epididymis

Moderate Unspecific

Moderate

During development and at adulthood

Moderate

Foster, P.M.D. and Harris, M.W.  2005.  Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages.  Toxicological Sciences 85: 1024–1032. Gray, Jr., L.E., Furr, J., Tatum-Gibbs, K.R., Lambright, C., Sampson, H., Hannas, B.R., Wilson, V.S., Hotchkiss, A., and Foster, P.M.D.  2016.  Establishing the “Biological Relevance” of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels.  Toxicological Sciences 149(1): 178–191. Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S.  2010.  Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats.  Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Welsh, M., Saunders, P.T.K., Fisken, M., Scott, H.M., Hutchison, G.R., Smith, L.R. and Sharpe, R.M.  2008.  Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.  Journal of Clinical Investigation 118(4): 1479-1490. Wilson, V.S., Howdeshell, K.L., Lambright, C.S., Furr, J., Gray, Jr., L.E.  2007.  Differential expression of the phthalate syndrome in male Sprague–Dawley and Wistar rats after in utero DEHP exposure.  Toxicology Letters 170: 177–184. NOTE: Italics symbolize edits from John Frisch     AOPWiki 2024-03-19T13:36:38

2024-04-16T11:52:01

Impaired, Spermatogenesis

Organ

Spermatogenesis is a multiphase process of cellular transformation that produces mature male gametes known as sperm for sexual reproduction (Xu et al., 2015). The process of spermatogenesis can be broken down into 3 phases: the mitotic proliferation of spermatogonia, meiosis, and post-meiotic differentiation(spermiogenesis) (Boulanger et al., 2015). Spermatogenesis can be impaired within these phases or due to external factors such as chemical exposures or the gonadal tissue environment. For example, zebrafish and fathead minnow exposed to flutamide, an antiandrogen, have shown signs of impaired spermatogenesis such as spermatocyte degradation(Jensen et al., 2004, Yin et al., 2017).

Impairment of spermatogenesis can be measured and detected in a multitude of ways. One example of this is qualitative histological assessments (Jensen et al., 2004). Through histology, sperm morphology can be examined and quantified through the number and stage of the sperm. Sperm morphology, overall quantity, and quantity within each stage can be ways to detect impaired spermatogenesis(Uhrin et al., 2000, Xie et al., 2020). Additionally, sperm quality can also be another assessment of impaired spermatogenesis such as sperm motility, velocity, ATP content, and lipid peroxidation(Gage et al., 2004, Xia et al., 2018, Chen et al., 2015). Impaired spermatogenesis can also be seen by measuring sperm density(Chen et al., 2015).

Taxonomic Applicability: The relevance for invertebrates has not been evaluated.  Life Stage Applicability: Only applicable for sexually mature adults Sex Applicability: Only applicable to males In vitro data is used to support these domains.

UBERON:0000473

UBERON testis

High Male

High

Adult, reproductively mature

High

Boulanger, G., Cibois, M., Viet, J., Fostier, A., Deschamps, S., Pastezeur, S., Massart, C., Gschloessl, B., Gautier-Courteille, C., & Paillard, L. (2015). Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice. Molecular and cellular biology, 35(18), 3244–3253. <a href="https://doi.org/10.1128/MCB.00074-15">https://doi.org/10.1128/MCB.00074-15</a> Chen, J., Xiao, Y., Gai, Z., Li, R., Zhu, Z., Bai, C., Tanguay, R. L., Xu, X., Huang, C., & Dong, Q. (2015). Reproductive toxicity of low level bisphenol A exposures in a two-generation zebrafish assay: Evidence of male-specific effects. Aquatic toxicology (Amsterdam, Netherlands), 169, 204–214. https://doi.org/10.1016/j.aquatox.2015.10.020 Golshan, M. & S.M.H. Alvai (2019) “Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders”, Theriogenology, Vol. 139, Elsevier, pp. 58-71. https://doi.org/10.1016/j.theriogenology.2019.07.020  Jensen, K.M. et al. (2004) “Characterization of responses to the antiandrogen flutamide in a short-term reproduction assay with the fathead minnow”, Aquatic Toxicology, Vol. 70(2), Elsevier, pp. 99-110. https://doi.org/10.1016/j.aquatox.2004.06.012  Uhrin, P., Dewerchin, M., Hilpert, M., Chrenek, P., Schöfer, C., Zechmeister-Machhart, M., Krönke, G., Vales, A., Carmeliet, P., Binder, B. R., & Geiger, M. (2000). Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility. The Journal of clinical investigation, 106(12), 1531–1539. <a href="https://doi.org/10.1172/JCI10768">https://doi.org/10.1172/JCI10768</a> Xia, H., Zhong, C., Wu, X., Chen, J., Tao, B., Xia, X., Shi, M., Zhu, Z., Trudeau, V. L., & Hu, W. (2018). Mettl3 Mutation Disrupts Gamete Maturation and Reduces Fertility in Zebrafish. Genetics, 208(2), 729–743. https://doi.org/10.1534/genetics.117.300574 Xie, H., Kang, Y., Wang, S., Zheng, P., Chen, Z., Roy, S., & Zhao, C. (2020). E2f5 is a versatile transcriptional activator required for spermatogenesis and multiciliated cell differentiation in zebrafish. PLoS genetics, 16(3), e1008655. https://doi.org/10.1371/journal.pgen.1008655 Xu, K., Wen, M., Duan, W., Ren, L., Hu, F., Xiao, J., Wang, J., Tao, M., Zhang, C., Wang, J., Zhou, Y., Zhang, Y., Liu, Y., & Liu, S. (2015). Comparative analysis of testis transcriptomes from triploid and fertile diploid cyprinid fish. Biology of reproduction, 92(4), 95. <a href="https://doi.org/10.1095/biolreprod.114.125609">https://doi.org/10.1095/biolreprod.114.125609</a> Yin, P. et al. (2017) “Diethylstilbestrol, flutamide and their combination impaired the spermatogenesis of male adult zebrafish through disrupting HPG axis, meiosis and apoptosis”, Aquatic Toxicology, Vol. 185, Elsevier, pp. 129-137. https://doi.org/10.1016/j.aquatox.2017.02.013 AOPWiki 2020-04-16T12:02:39

2024-04-10T17:41:09

<upstream-id>00aad648-552a-4555-a84b-727165f45f40</upstream-id> <downstream-id>cdd707fb-b45c-4fee-bd68-5a7ffdafef04</downstream-id> In this key event relationship we are focused on the decrease in Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) gene expression, and corresponding decreased activity of steroidogenesis genes involved in the synthesis of steroid compounds.  COUP-TFII is also known as also known as Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) (Mendoza-Villarroel et al. 2014).

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Palermo et al. (2021) focused on identifying Adverse Outcome Pathways associated with adverse male reproductive outcomes from phthalate exposure through review of existing literature, and provided initial network analysis.  Authors of KER 3167 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

The biological plausibility linking decrease of COUP-TFII gene expression to decreased steroidogenesis is strong.   Predominately in laboratory mammal studies, COUP-TFII gene expression has been studied via toxicant exposure as well as contrasting wild-type strains to strains with decreased COUP-TFII function, and consistently shown decreased steroidogenic activity.

Moderate Unspecific

Moderate

All life stages

Moderate

Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064.   NOTE: Italics symbolize edits from John Frisch AOPWiki 2024-03-20T08:44:39

2024-04-16T09:39:41

<upstream-id>cdd707fb-b45c-4fee-bd68-5a7ffdafef04</upstream-id> <downstream-id>2ccf0058-bf1d-488d-aa59-fecc00ef20f1</downstream-id> In this key event relationship we are focused on the decrease in activity of steroidogenesis genes involved in the synthesis of steroid compounds and corresponding decrease in testosterone levels.  A large number of genes are involved in regulating steroidogenesis, so here we present evidence from available empirical studies.  Decreased testosterone levels are most often noted as resulting from decreases in expression of genes in the StAR, Cyp11, Cyp17, p450, HSD3β, and SR-B1 gene families.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Palermo et al. (2021) focused on identifying Adverse Outcome Pathways associated with adverse male reproductive outcomes from phthalate exposure through review of existing literature, and provided initial network analysis.  Authors of KER 3168 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

The biological plausibility linking decreased gene expression associated with steroidogenesis to decreased testosterone levels is strong.   Predominately in laboratory mammal studies, gene expression has been studied via toxicant exposure as well as contrasting wild-type strains to strains with knockout gene function, and consistently shown decreased testosterone levels.

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:97px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:69px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:110px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Decreased Steroidogenic Enzymes? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:71px"> Decreased Testosterone? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:109px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:77px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 4-6 months </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> Gene knockout study </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Wild-type and Cyp17a1 knock out-mice, decreased Cyp17a1 gene expression (involved in steroid biosynthesis) and decreased testosterone levels in XY mice. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Aherrarhou et al. (2020) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 7 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 500 mg/kg/day DBP in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Crl:CD(SD)BR rats, decreased steroidogenic acute regulatory (STAR) gene expression, hormone levels of p450scc, 3B-HSD, P450c17 involved in steroid biosynthesis and resulting decreased testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Barlow et al. (2003) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 15 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 10,30,100,300 mg/kg/day DEHP in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Wistar rats, dose-dependent decrease in gene and protein expression of StAR, PBR, P450scc, decreased SR-B1 and P450c17 gene expression (involved in steroid biosynthesis) and resulting decreased testosterone levels </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Borch et al. (2006) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 3 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 1,10,100 uM explanted fetal testes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Sprague-Dawley rats, dose-dependent effect on Cyp17a1 gene expression and protein levels, decreased gene expression of FDX1 (involved in steroid biosynthesis) and corresponding decreases in testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Chauvigné et al. (2011) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 50 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> NR dose, sodium arsenite exposure in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> CD-1 mice, decreased Star gene expression involved in steroid biosynthesis, resulting decrease in testosterone levels </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Clark et al. (2007) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 5 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 100,500 mg/kg DBP, 100 ug/kg dexamethasone and mixture of DBP and dexamethasone in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Wistar rats, dose-dependent decrease in gene expression of StAR, CYP11A1 (involved in steroid biosynthesis) and resulting decrease in testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Drake et al. (2009) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 5 days in utero; juvenile - adulthood </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 0,11,33,300 mg/kg/d DPeP in utero and juvenile-adulthood </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Harlan Sprague-Dawley rats, dose-dependent decrease in gene expression of Cyp11b1, StAR, Cyp17a1, Cyp11a1, Hsd3b, other genes involved in steroid biosynthesis and resulting decrease in testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Gray et al. (2016) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 5 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 100,300,600,900 mg/kg/d DHeP, DHP in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Sprague-Dawley rats, dose-dependent decrease in gene expression of Star, Cyp11a1, Hsd3b, Cyp17a1, Cyp11b1 (involved in steroid biosynthesis) and resulting decrease in testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Hannas et al. (2012) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 24 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 100, 500 mg/kg DEP in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Sprague-Dawley rats, dose-dependent decrease in gene expression of SR-B1, StAR, CYP17A1, CYP11A1 (involved in steroid biosynthesis) and resulting decrease in testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Kuhl et al. (2007) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 6 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 0.01,0.1,1,10,100,1000 mg/kg/day DPT in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Sprague-Dawley rats, dose-dependent decrease in gene expression of SR-B1, StAR, P450scc, CYP17, 3βHSD involved in steroid biosynthesis, dose-dependent decrease in protein of SR-B1, STAR, P450scc, CYP17 and resulting decreased testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Lehman et al. (2004) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 40 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> Knock-out gene study </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> CD1-mice, various cell lines with wild-type and knock-out gene expression, decreased steroidogenic acute regulatory (STAR) gene expression and resulting decreased testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Mendoza-Villarroel et al. (2014) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 3 months </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 1 mg/50 g bw tamoxifen for 5 consecutive days in utero, knock-out gene study, juvenile exposure. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> COUP-TFII flox/flox mice and CAGG-Cre-ERTM mice, tamoxifen exposure, decreased 3β-HSD, 450Scc, and CYP17 gene expression, genes related to steroid biosynthesis and resulting decreased testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Qin et al. (2008) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 6 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 500 mg/kg/day DBP in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Sprague-Dawley rats, decreased gene and protein expression SR-B1, StAR, SCC, CYP17 (related to steroid biosynthesis) and resulting decreased testosterone levels, additional experiment showed restoration of SR-B1, StAR, SCC, CYP17 protein levels after 48 hours withdrawal of DBP </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> Thompson et al. (2004) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:97px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:69px"> 8 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:110px"> 20, 100, 500 mg/kg/day DBP, 100 ug/kg/day dexamethasone, 100 ug/kg diethylstilbestrol every other day, mixture 500 mg/kg/day DBP plus 100 ug/kg day dexamethasone in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:71px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:109px"> Wistar rats, dose-dependent response decreased STAR, CYP17, CYP11 gene expression, genes related to steroid biosynthesis and resulting decreased testosterone levels. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:77px"> van den Driesche et al. (2012) </td> </tr> </tbody> </table>

Moderate Unspecific

Moderate

All life stages

Moderate

Aherrarhou, R., Kulle, A.E., Alenina, N., Werner, R., Vens-Cappell, S., Bader, M., Schunkert, H., Erdmann, J., and Aherrarhou, Z.  2020.  Nature Scientific Reports 10: 8792. Barlow, N.J., Phillips, S.L., Wallace, D.G., Sar, M., Gaido, K.W., and Foster, P.M.D.  2003.  Quantitative Changes in Gene Expression in Fetal Rat Testes following Exposure to Di(n-butyl) Phthalate.  Toxicological Sciences 73: 431-451. Borch, J., Metzdorff, S.B., Vinggard, A.M., Brokken, L., and Dalgaard, M.  2006.  Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis.  Toxicology 223 (2006) 144–155. Chauvigné, F., Plummer, S., Lesné, L., Cravedi, J.-P., Dejucq-Rainsford, N., Fostier, A., and Jégou, B.  2011.   Mono-(2-ethylhexyl) Phthalate Directly Alters the Expression of Leydig Cell Genes and CYP17 Lyase Activity in Cultured Rat Fetal Testis.  Public Library of Science One 6(11): e27172. Clark, B.J. and Cochrum, R.K.  2007.  The Steroidogenic Acute Regulatory Protein as a Target of Endocrine Disruption in Male Reproduction. Drug Metabolism Reviews 39(2-3): 353-370. Drake, A.J., van den Driesche, S., Scott, H.M., Hutchinson, G.R., Seckl, J.R. and Sharpe, R.M.  2009.  Glucocorticoids Amplify Dibutyl Phthalate-Induced Disruption of Testosterone Production and Male Reproductive Development.  Endocrinology 150(11): 5055–5064. Gray, Jr., L.E., Furr, J., Tatum-Gibbs, K.R., Lambright, C., Sampson, H., Hannas, B.R., Wilson, V.S., Hotchkiss, A., and Foster, P.M.D.  2016.  Establishing the “Biological Relevance” of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels.  Toxicological Sciences 149(1): 178–191. Hannas, B.R., Lambright, C.S., Furr, J., Evans, N. Foster, P.M.D., Gray, E.L., and Wilson, V.S.  2012.  Genomic Biomarkers of Phthalate-Induced Male Reproductive Developmental Toxicity: A Targeted RT-PCR Array Approach for Defining Relative Potency.  Toxicological Sciences 125(2): 544–557. Kuhl, A.J., Ross, S.M., and Gaido, K.W.  2007.  CCAAT/Enhancer Binding Protein β, But Not Steroidogenic Factor-1, Modulates the Phthalate-Induced Dysregulation of Rat Fetal Testicular Steroidogenesis.  Endocrinology 148(12): 5851–5864. Lehmann, K.P., Phillips, S., Sar, M., Foster, P.M.D., and Gaido, K.W.  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 81: 60-68. Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. Thompson, C.J., Ross, S.M., and Gaido, K.W.  2004.  Di(n-Butyl) Phthalate Impairs Cholesterol Transport and Steroidogenesis in the Fetal Rat Testis through a Rapid and Reversible Mechanism.  Endocrinology 145(3):1227–1237. van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064. NOTE: Italics symbolize edits from John Frisch   AOPWiki 2024-03-20T08:45:25

2024-04-05T13:39:08

<upstream-id>2ccf0058-bf1d-488d-aa59-fecc00ef20f1</upstream-id> <downstream-id>5525871b-79c2-45cc-b096-e7b07caca844</downstream-id> In this key event relationship we are focused on the decrease in testosterone levels and resulting increase in epididymal agenesis and malformation of epididymis.  Decreases in testosterone levels can cause a host of developmental issues, but here we present evidence from empirical studies in which induced decreases in testosterone result in abnormal epididymis development.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Palermo et al. (2021) focused on identifying Adverse Outcome Pathways associated with adverse male reproductive outcomes from phthalate exposure through review of existing literature, and provided initial network analysis.  Authors of KER 3169 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

The biological plausibility linking decreased testosterone levels to increased epidydimal agenesis is strong.  Predominately in laboratory mammal studies, testosterone levels and resulting histological malformations have been studied via toxicant exposure (especially from phthalates), and shown a consistent response with increased agenesis and problems with epidydimal malformation.

Moderate Unspecific

High

Development

Moderate

Life Stage: Occurs during development. Sex: Applies to both males and females. Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.

Gray, Jr., L.E., Furr, J., Tatum-Gibbs, K.R., Lambright, C., Sampson, H., Hannas, B.R., Wilson, V.S., Hotchkiss, A., and Foster, P.M.D.  2016.  Establishing the “Biological Relevance” of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels.  Toxicological Sciences 149(1): 178–191. Hotchkiss, A.K., Parks-Saldutti, L.G., Ostby, J.S., Lambright, C., Furr, J., Vandenbergh, J.G., and Gray, Jr., L.E.  2004.  A Mixture of the ‘‘Antiandrogens’’ Linuron and Butyl Benzyl Phthalate Alters Sexual Differentiation of the Male Rat in a Cumulative Fashion.  Biology of Reproduction 71: 1852–1861. Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S.  2010.  Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats.  Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. Wilson, V.S., Howdeshell, K.L., Lambright, C.S., Furr, J., Gray, Jr., L.E.  2007.  Differential expression of the phthalate syndrome in male Sprague–Dawley and Wistar rats after in utero DEHP exposure.  Toxicology Letters 170: 177–184. NOTE: Italics symbolize edits from John Frisch   AOPWiki 2024-03-20T08:45:43

2024-04-08T15:40:51

<upstream-id>5525871b-79c2-45cc-b096-e7b07caca844</upstream-id> <downstream-id>8525e4da-df08-4ab0-96b4-49c2ee8b557b</downstream-id> In this key event relationship we are focused on epididymal agenesis and malformation of epididymis, and resulting impairment of spermatogenesis.  During development issues arise with organ formation, with resulting impairment observed in mature individuals.  Impaired spermatogenesis results in a number of issues, including decreased sperm count, increased number of abnormal sperm, and limited regions in which sperm are able to develop.

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Palermo et al. (2021) focused on identifying Adverse Outcome Pathways associated with adverse male reproductive outcomes from phthalate exposure through review of existing literature, and provided initial network analysis.  Authors of KER 3170 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

The biological plausibility linking issues with epididymis formation to impaired spermatogenesis is strong.  Predominately in laboratory mammal studies, malformations from toxicant exposure or genetic damage have resulted in a variety of types of spermatogenesis impairment.  Empirical studies generally examine sperm counts, the number of abnormal sperm, and whether germ cell formation is limited.

High Male

Moderate

During development and at adulthood

Moderate

Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals.  Sex: Applies to males. Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.

Barlow, N.J. and Foster, P.M.D.  2003b.  Pathogenesis of Male Reproductive Tract Lesions from Gestation Through Adulthood Following in Utero Exposure to Di(n-butyl) Phthalate.  Toxicologic Pathology 31:397–410. Foster, P.M.D. and Harris, M.W.  2005.  Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages.  Toxicological Sciences 85: 1024–1032. Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S.  2010.  Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats.  Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559. Lee, K.-Y., Shibutani, M., Takagi, H., Kato, N., Takigami, S., Uneyama, C., and Horose, M.  2003.  Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation.  Toxicology 203: 221–238. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. Zhang, Y., Jiang, X., and Chen, B.  2004.  Reproductive and developmental toxicity in F1 Sprague–Dawley male rats exposed to di-n-butyl phthalate in utero and during lactation and determination of its NOAEL.  Reproductive Toxicology 18: 669–676. NOTE: Italics symbolize edits from John Frisch   AOPWiki 2024-03-20T08:46:06

2024-04-08T16:19:02

Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Impaired, Spermatogenesis

Decreased COUP-TFII in Leydig cells leads to Impaired, Spermatogenesis

Arthur Author

Of the originating work: Christine M. Palermo and Jennifer E. Foreman, ExxonMobile; Daniele S. Wikoff, Isabel Lea, ToxStrategies. Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division.

BY-SA

2.6

Impaired spermatogenesis is an adverse outcome often observed among a group of male reproductive abnormalities caused by organ malformation (epididymis, vas deferens, seminal vesicles, prostate, external genitalia) during development (Drake et al. 2009; Palermo et al. 2021).  These reproductive abnormalities have been observed in studies of laboratory mice and rats exposed to phthalates during in utero development, in attempts to understand the gene expression/inhibition, hormone levels, and other factors leading to the observed adverse outcomes.  Studies in laboratory mammals have allowed researchers to target the role of individual genes by knockout gene studies, and target critical developmental windows by timed exposure to toxicants, to explore the mechanisms leading to reproductive defects similar to human birth defects observed in clinical studies (Review in Foster 2006).  Although a molecular initiating event isn’t well established, decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII)) gene expression has been linked to decreased expression of genes coding for enzymes involved in steroidogenesis and decreased testosterone levels in mammals (Qin et al. 2008; van den Driesche et al. 2012; Mendoza-Villarroel et al. 2014).  One adverse outcome of decreased testosterone, and the focus of this adverse outcome pathway, is epididymal agenesis, and resulting impaired spermatogenesis (Mahood et al. 2007; Qin et al. 2008; Kim et al. 2010).  Impaired spermatogenesis results in decreased sperm counts, as well as decreases in the number of sperm capable of fertilization (Barlow and Foster 2003). This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271.  This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.  Phthalates are of increasing human health concern because of increased use and accumulating evidence of disruption of reproductive development in vertebrates.  First detected in laboratory mammals, exposure to phthalates and other toxicants in utero when male sexual differentiation is occurring have resulted in increased malformation of reproductive organs, failure of male characteristics to develop, and failure of proper positioning of organs (ex. hypospadias and cryptorchidism).  Clinical studies in humans have used laboratory mammal data to help understand and treat conditions exhibited by individual people.   This AOP focuses on the pathway leading to impaired to spermatogenesis, via abnormal formation of the epididymis, decreased testosterone levels, and initiated by decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) gene expression and subsequent disrupted signaling for steroidogenesis. The focus of the originating work was to use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).  Palermo et al. (2021) provided network analysis based on two literature searches: 1. rodent male reproductive development abnormalities using key terms; 2. effects of low molecular weight phthalates (LMWPs) during the rodent male programming window (MPW) of development.  Relevant key events and key event relationships were narrowed by focusing on empirical studies related to ‘rat phthalate syndrome’ which resulted in 3 recommended Adverse Outcome Pathways: 1. INSL expression to cryptorchidism (see AOP 528 for related content); 2. COUP-TFII expression to hypospadias (see AOP 527 for related content); 3. COUP-TFII expression to altered sperm maturation (see this AOP 526 for related content).

The originating authors conducted a literature search to develop a database of publications categorized by discipline or field of study: toxicology, epidemiology, exposure, and gene-environment interaction. The literature search relied on standard search engines such as Web of Science and Google Scholar, and the search strategy focused on toxicants known to disrupt lipid pathways in organisms, and diet studies with elevated levels of lipids. The originating authors reviewed references from individual citations to identify additional studies not captured through the literature search itself. They then included all relevant publications through 2023. Only studies focused primarily on developmental or neurotoxic endpoints were included; those focused on carcinogenesis or other systemic effects were not included unless there was a particular relevance to a neurotoxic or developmental outcome. The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.     <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/04/23/7d3mwuiavf_Citation_workflow_graphic.png" /> The authors of AOP 526 also referred to existing AOP-wiki content on disruption of steroidogenesis pathways, especially work by Gary Klinefelter (ex. AOP 70, 71).  We found existing Adverse Outcome Pathway content documented different series of key events then the pathways provided by Palermo et al. (2021), and therefore initiated AOP 526 and updated existing AOP-wiki key events when available.

adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High

High Male

High

During development and at adulthood

Moderate

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top"> 1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship  between KEup and KEdown consistent with established biological knowledge? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support   Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3167: Decreased COUP-TFII in Leydig cells, leads to Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between decrease in COUP-TFII expression and decreased steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR) is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3168: Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells leads to Decrease, testosterone levels </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between decreased steroidogenic enzymes and decreased testosterone is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3169: Decrease, testosterone levels leads to Epididymal Agenesis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Decreased testosterone levels have consistently been linked to epididymal agenesis and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3170: Epididymal Agenesis leads to Impaired, Spermatogenesis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Epididymal agenesis and improper formation of the epididymis has been shown to results in impaired spermatogenesis (decreased sperm counts and function) across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Extensive understanding of the relationships between events from empirical studies from a variety of taxa, including frequent testing in lab mammals. </td> </tr> </tbody> </table> Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals. Sex: Applies to males. Taxonomic: Appears to be present broadly in mammals, with most representative studies in mammals (humans, lab mice, lab rats).

<table cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:775px"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> 2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event (KE) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events. Moderate = Indirect evidence from experimental studies inferring essentiality of relationship between key events due to difficulty in directly measuring at least one of key events. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 656: Decreased COUP-TFII in Leydig cells </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate support.  Decrease in COUP-TFII expression has been linked to decreased steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR).  Evidence is available from toxicant, gene-knockout, and protein studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 647 Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Decreased expression of steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR is linked to decreased testosterone levels.   Evidence is available from toxicant, gene-knockout, and protein studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 1690 Decrease, testosterone levels </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate support.  Decreases in testosterone have been correlated with epididymal agenesis and abnormal development of epididymides.  Evidence is available from toxicant and histology studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 2212 Epididymal Agenesis </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Malformed epididymides and epididymal agenesis is linked to impaired spermatogenesis.  Evidence is available from toxicant and histology studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> AO 1758 Impaired, Spermatogenesis </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Impaired spermatogenesis is often caused by development issues in formation of reproductive tissues including epididymides.  Evidence is available from toxicant and histology studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate to strong support.  Direct evidence from empirical studies from laboratory mammals for most key events, with more inferential evidence for gene expression and protein studies. </td> </tr> </tbody> </table>

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> 3. Empirical Support for Key Event Relationship: Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support  Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions.  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3167: Decreased COUP-TFII in Leydig cells, leads to Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Decreases in COUP-TFII expression lead to decreased steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR, primarily from studies examining COUP-TFII knock-out genes, as well as changes in gene expression/protein levels after exposure to chemical stressors. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3168: Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells leads to Decrease, testosterone levels </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Decreases in steroidogenesis enzymes lead to decreases in testosterone levels, primarily from studies measuring gene expression and correlation to protein and hormone levels. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3169: Decrease, testosterone levels leads to Epididymal Agenesis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Decreases in testosterone have been correlated with malformation and agenesis of epididymides through measurement of hormone levels, and resulting issues in reproductive tissue formation. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3170: Epididymal Agenesis leads to Impaired, Spermatogenesis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Malformation of epididymides directly impacts ability of the organ to develop normal numbers of functional sperm. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Exposure from empirical studies shows consistent change in both events from a variety of taxa, including frequent testing in lab mammals. </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Barlow, N.J. and Foster, P.M.D.  2003.  Pathogenesis of Male Reproductive Tract Lesions from Gestation Through Adulthood Following in Utero Exposure to Di(n-butyl) Phthalate.  Toxicologic Pathology 31:397–410. Drake, A.J., van den Driesche, S., Scott, H.M., Hutchinson, G.R., Seckl, J.R. and Sharpe, R.M.  2009.  Glucocorticoids Amplify Dibutyl Phthalate-Induced Disruption of Testosterone Production and Male Reproductive Development.  Endocrinology 150(11): 5055–5064. Foster, P.M.D.  2006. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters.  International Journal of Andrology 29: 140–147. Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S.  2010.  Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats.  Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559. Mahood, I.K., Scott, H.M., Brown, R., Hallmark, N., Walker, M., and Sharpe, R.M.  2007.  In Utero Exposure to Di(n-butyl) Phthalate and Testicular Dysgenesis: Comparison of Fetal and Adult End Points and Their Dose Sensitivity.  Environmental Health Perspectives 115 (supplement 1): 55-61. Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12. Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271. Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285. van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064.   AOPWiki 2024-03-19T11:09:36

2024-05-26T20:40:00