Inhibition, Cytochrome P450 enzyme (CYP17A1) activity

WCS_9606

common toxicological species human

10116

NCBI rat

WikiUser_17

mammals

10090

NCBI mouse

Inhibition, Cytochrome P450 enzyme (CYP17A1) activity

Inhibition of Cyp17A1 activity

Molecular

Cyp17a1 inhibitors bind in the active site of the enzyme by mimicking endogenous substrate, leading to a reduction in the activity of the enzyme. Cyp17A1 is the single enzyme mediating both 17 alpha-hydroxylase and 17,20-lyase activities, the distinction between the two being functional and not genetic or structural.  Cyp17a1 is found in all the steroidogenic tissues such as the Leydig cells of the testes, the thecal cells of the ovaries and the adrenal cortex. Studies also detected Cyp17a1 activities in  heart, adipose, liver and kidney tissue. CYP17a1 has a decisive function in steroidogenesis by constituting the initial step in a series of biochemical reactions that culminate in synthesis of steroid end-products (testosterone, estradiol, cortisol, and DHEA). Thus, any variation in Cyp17a1’s activity directly or indirectly affect steroidogenesis.12

Measurement in CYP17 MA-10 wild-type and CYP17 knock down MA-10 clone can be used to assess the effects of a dysfunction in CYP17a1 activity.3

1 Storbeck K., Swart P., Africander D., Conradie R., Louw R. and.Swart A.C. (2011) 16α-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction. Molecular and Cellular Endocrinology, 336(1-2): 92-101<a href="https://www.google.com/url?q=https://doi.org/10.1016/j.mce.2010.11.016&sa=D&ust=1554888093195000">https://doi.org/10.1016/j.mce.2010.11.016</a> 2 Petrunak E.M., DeVore N.M., Patrick R. Porubsky PR.., and Scott E.E.(2014) Structures of human steroidogenic cytochrome P450 17A1 with substrates. Journal of Biological Chemistry, 289(47): 32952–32964  <a href="https://www.google.com/url?q=https://doi.org/10.1074/jbc.M114.610998&sa=D&ust=1554888093196000" style="font-size: 14px;">https://doi.org/10.1074/jbc.M114.610998</a>  3 Liu Y., Yao ZX., and Papadopoulos V. (2005) Cytochrome P450 17α Hydroxylase/17,20 Lyase (CYP17) Function in Cholesterol Biosynthesis: Identification of Squalene Monooxygenase (Epoxidase) Activity Associated with CYP17 in Leydig Cells. Molecular Endocrinology, 19(7): 1918-1931 <a href="https://www.google.com/url?q=https://doi.org/10.1210/me.2004-0271&sa=D&ust=1554888093196000">https://doi.org/10.1210/me.2004-0271</a>  4 Anitha B. Alex, Sumanta K. Pal, and Neeraj Agarwal (2016) CYP17 inhibitors in prostate cancer: latest evidence and clinical potential. Therapeutic Advances in Medical Oncology, 8(4):267-75  <a href="https://www.google.com/url?q=https://doi.org/10.1177/1758834016642370&sa=D&ust=1554888093193000">https://doi.org/10.1177/1758834016642370</a> 5 Roelofs M.J., Piersma A.H., van den Berg M. and van Duursen M.B. (2013) The relevance of chemical interactions with CYP17 enzyme activity: assessment using a novel in vitro assay. Toxicology and Applied Pharmacology 1;268(3):309-17 <a href="https://www.google.com/url?q=https://doi.org/10.1016/j.taap.2013.01.033&sa=D&ust=1554888093194000">https://doi.org/10.1016/j.taap.2013.01.033</a>  6 Vinggaard A.M., Christiansen S., Laier P., Poulsen M.E., Breinholt V, Jarfelt K., Jacobsen H., Dalgaard M., Nellemann C. and Hass U. (2005) Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring. Toxicological Sciences, 85:886–897<a href="https://www.google.com/url?q=https://doi.org/10.1093/toxsci/kfi150&sa=D&ust=1554888093194000">https://doi.org/10.1093/toxsci/kfi150</a>  AOPWiki 2019-04-10T04:54:54

2019-04-10T05:13:42

Reduction, 17-OH-pregnenolone conversion in DHEA

Reduction, DHEA

Cellular

17-OH-pregnenolone is the direct precursor of dehydroepiandrosterone (DHEA), a reduction in its synthesis results in a decrease in DHEA level. DHEA is defined as an obligatory intermediate in sex steroid biosynthesis being the precursor of steroid hormones like testosterone and estradiol.12

17-OH-pregnenolone and DHEA can be fractionated using High Performance Liquid Chromatography. After separation, pregnenolone and DHEA levels can be quantify using immunoassay such as ELISA or Radio Immuno Assay (RIA). For both steroids, LC-MS/MS is also an option.

1 Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318. <a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&sa=D&ust=1554888093201000">https://doi.org/10.1210/edrv-9-3-295</a>  2 Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.<a href="https://www.google.com/url?q=https://doi.org/10.1210/er.2010-0013&sa=D&ust=1554888093202000">https://doi.org/10.1210/er.2010-0013</a>  AOPWiki 2019-04-10T04:59:05

2019-04-10T05:15:50

Reduction, 17-OH-progesterone conversion in androstenedione

Reduction, androstenedione

Cellular

17-OH-progesterone is the direct precursor of  androstenedione, a reduction in its synthesis results in a decrease in androstenedione levels. Androstenedione is defined as an obligatory intermediate in sex steroid biosynthesis being the precursor of steroid hormones like testosterone and estradiol. 12

Competitive immunoenzymatic colorimetric methods (ELISA) for quantitative determination of 17-OH-progesterone and androstenedione concentration in serum or plasma are available. Progesterone and androstenedione synthesis can be monitored using radiolabeled steroid precursor in association with High Performance Liquid Chromatography (HPLC). During synthesis, steroids will incorporate the radioactive label which can be afterwards, used for quantification. First of all, HPLC combined with internal standards can be used for steroids collection, fractionation and identification. Once separated from the other steroids, progesterone and androstenedione can be finally quantified using liquid scintillation spectrometry.

<table> <tbody> <tr> <td colspan="1" rowspan="1">   </td> <td colspan="1" rowspan="1"> 1 Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318. <a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&sa=D&ust=1554891396596000">https://doi.org/10.1210/edrv-9-3-295</a>  2 Liu Y., Yao ZX., and Papadopoulos V. (2005) Cytochrome P450 17α Hydroxylase/17,20 Lyase (CYP17) Function in Cholesterol Biosynthesis: Identification of Squalene Monooxygenase (Epoxidase) Activity Associated with CYP17 in Leydig Cells. Molecular Endocrinology, 19(7): 1918-1931 <a href="https://www.google.com/url?q=https://doi.org/10.1210/me.2004-0271&sa=D&ust=1554891396596000">https://doi.org/10.1210/me.2004-0271</a>  </td> </tr> </tbody> </table>   AOPWiki 2019-04-10T05:01:12

2019-04-10T05:33:19

Decrease, testosterone synthesis/level

Decrease, testosterone level

Cellular

Reduction in testosterone synthesis leads to a reduction in testosterone circulating levels. 12

ELISA kit can be used for quantitative measurement of testosterone in various samples. Liquid Chromatography- tandem Mass Spectrometry is also an option. 3 Detection of increase and decrease in the production of testosterone after chemical exposure can be measured using the validated H295R Steroidogenesis Assay associated with hormone measurement kits (ELISA) and/or instrumental techniques (LC-MS). 4 Testosterone (T) levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, testosterone can be identified by comparison with internal standards spectrum. Quantification of T levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling).

<table> <tbody> <tr> <td colspan="1" rowspan="1">   </td> <td colspan="1" rowspan="1"> 1 Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318. <a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&sa=D&ust=1554891396604000">https://doi.org/10.1210/edrv-9-3-295</a>  2 Elder P.A. and Lewis J.G. (1985) An enzyme-linked immunosorbent assay (ELISA) for plasma testosterone. Journal of steroid biochemistry, 22(5):635-8. 3 Shiraishi S., Lee P.W., Leung A., Goh V.H., Swerdloff R.S. and Wang C. (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical chemistry, 54(11): 1855-63.<a href="https://www.google.com/url?q=https://doi.org/10.1373/clinchem.2008.103846&sa=D&ust=1554891396605000">https://doi.org/10.1373/clinchem.2008.103846</a>  4 OECD Guideline For the Testing of Chemicals - H295R Steroidogenesis Assay (2011)<a href="https://www.google.com/url?q=https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-tg456-2011-508.pdf&sa=D&ust=1554891396606000">https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-tg456-2011-508.pdf</a>  </td> </tr> </tbody> </table> AOPWiki 2019-04-10T05:02:08

2019-04-10T05:20:33

Decrease, dihydrotestosterone (DHT) level

Decrease, DHT level

Cellular

Reduction in DHT synthesis leads to a reduction in DHT circulating levels. 12

DHT levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, DHT can be identify by comparison with internal standards spectrum. Quantification of DHT levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling).3

<table> <tbody> <tr> <td colspan="1" rowspan="1"> 1 Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318.<a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&sa=D&ust=1554891396614000">https://doi.org/10.1210/edrv-9-3-295</a>    2 Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.<a href="https://www.google.com/url?q=https://doi.org/10.1210/er.2010-0013&sa=D&ust=1554891396616000">https://doi.org/10.1210/er.2010-0013</a>    3 Shiraishi S., Lee P.W., Leung A., Goh V.H., Swerdloff R.S. and Wang C. (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical chemistry, 54(11): 1855-63.<a href="https://www.google.com/url?q=https://doi.org/10.1373/clinchem.2008.103846&sa=D&ust=1554891396617000">https://doi.org/10.1373/clinchem.2008.103846</a> </td> </tr> </tbody> </table> AOPWiki 2019-04-10T05:02:29

2019-04-10T05:22:55

Decrease, androgen receptors (AR) activation

Decrease, AR activation

Cellular

Androgen receptor activation is regulated by the binding of androgens. AR activity can be decreased by either a lack of steroidal ligands (testosterone, DHT) or the presence of antagonist compounds. 12

Significance of AR signaling in fetal development can be studied through a conditional deletion of the androgen receptor using a Cre/loxP approach. The recommended animal model for reproductive study is the mouse.3 Also, epidemiological case-studies following mouse or humans expressing a complete androgen insensitivity allow to directly assess the effects of a lack of AR activation on the development.4 Enzyme immunoassay (ELISA) kits for in vitro quantitative measurement of AR activity are available. Androgen receptors activity can be measured using bioassay such as the (Anti-)Androgen Receptor CALUX reporter gene assay.5

<table> <tbody> <tr> <td colspan="1" rowspan="1">   </td> <td colspan="1" rowspan="1"> 1 Davey R.A and Grossmann M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clinical Biochemist Reviews, 37(1): 3-15. PCM4810760 2 Gao W., Bohl C.E. and Dalton J.T. (2005) Chemistry and Structural Biology of Androgen Receptor. Chemical Reviews 105(9): 3352-3370<a href="https://www.google.com/url?q=https://doi.org/10.1021/cr020456u&sa=D&ust=1554891396627000">https://doi.org/10.1021/cr020456u</a>  3 Kaftanovskaya E.M., Huang Z., Barbara A.M., De Gendt K., Verhoeven G., Ivan P. Gorlov, and Agoulnik A.I. (2012) Cryptorchidism in Mice with an Androgen Receptor Ablation in Gubernaculum Testis. Molecular Endocrinology, 26(4): 598-607.<a href="https://www.google.com/url?q=https://doi.org/10.1210/me.2011-1283&sa=D&ust=1554891396628000">https://doi.org/10.1210/me.2011-1283</a>  4 Hutson J.M. (1985) A biphasic model for the hormonal control of testicular descent. Lancet, 24;2(8452): 419-21<a href="https://www.google.com/url?q=http://dx.doi.org/10.1016/S0140-6736(85)92739-4&sa=D&ust=1554891396629000">http://dx.doi.org/10.1016/S0140-6736(85)92739-4</a>  5 van der Burg B., Winter R., Man HY., Vangenechten C., Berckmans P., Weimer M., Witters M. and van der Linden S. (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive Toxicology, 30(1):18-24 <a href="https://www.google.com/url?q=https://doi.org/0.1016/j.reprotox.2010.04.012&sa=D&ust=1554891396630000">https://doi.org/0.1016/j.reprotox.2010.04.012</a>  </td> </tr> </tbody> </table> AOPWiki 2019-04-10T05:04:18

2019-04-10T05:24:20

Impaired inguinoscrotal testicular descent phase

Impaired inguinoscrotal phase

Organ

Testis descent is based on a two-phase process: the transabdominal phase (INSL3-mediated) and the inguinoscrotal phase (Androgen-dependent). The transabdominal phase takes place in the first months of pregnancy, between 10 and 15 weeks. The inguinoscrotal phase occurs later in the fetus development, about 25-35 weeks of gestation. During this second phase, the testis is supposed to get into the scrotum. A defect in the inguinoscrotal phase results in a dysfunction in testis migration: the testis is stuck in the abdominal part of the body.1 Any impairment in testis migration, either through the transabdominal phase or the inguinoscrotal phase, will directly result in the absence of one or both testes from the scrotum.

1 Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325 <a href="https://www.google.com/url?q=https://doi.org/10.1007/s00383-015-3673-4&sa=D&ust=1554891396640000">https://doi.org/10.1007/s00383-015-3673-4</a>  AOPWiki 2019-04-10T05:05:26

2019-04-10T05:25:15

Malformation, cryptorchidism - maldescended testis

Malformation, cryptorchidism

Organ

Undescended testis is a testicular disorder syndrome known as  cryptorchidism. Testis migration is a major event in male fetus development, as it will directly affect his reproductive health. Cryptorchidism can defined itself as the insertion of the testis in another position than the scrotum. Although the events leading to this pathology occurred during development, cryptorchidism can only be defined after birth though clinical examination as palpation. Cryptorchidism can be either uni- or bilateral and has been reported to increase in incidence over the decades (Denmark, UK, India…). The maldescended testis will experiment heat stress (37 against 33C outside the body) interfering with testicular physiology and development of germ cells into spermatogonia. Germ cells maturation failure will induce a non-reversible reduction in fertility power of the individual. Cryptorchidism is an established risk factor for infertility and is known to increase the incidence of testicular germ cell tumors (TGCT) 123   Remark:  <table> <tbody> <tr> <td colspan="1" rowspan="1"> Cryptorchidism is the first AO of a larger list including raise in testicular cancer and germ cell tumor incidence, as well as reduced fertility due to impairment in germ cells maturation. </td> </tr> </tbody> </table>

Cryptorchidism is a birth defect that can be highlighted by a clinical examination. The aim of this palpation is to locate the gonad and determine its lowest position without causing painful traction on the spermatic cord. 4

1 Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325. <a href="https://www.google.com/url?q=https://doi.org/10.1007/s00383-015-3673-4&sa=D&ust=1554891396648000">https://doi.org/10.1007/s00383-015-3673-4</a>  2 Boisen K.A., Kaleva M., Main K.M., Virtanen H.E., Haavisto A.M., Schmidt I.M., Chellakooty M., Damgaard I.N., Mau C., Reunanen M., Skakkebaek N.E. and Toppari J. (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet, 17;363(9417):1264-9 <a href="https://www.google.com/url?q=https://doi.org/10.1016/S0140-6736(04)15998-9&sa=D&ust=1554891396649000">https://doi.org/10.1016/S0140-6736(04)15998-9</a>  3 Acerini C.L., Miles H.L., Dunger D.B., Ong K.K. and Hughes I.A. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Archives of disease in childhood, 94(11):868-72 https://doi.org10.1136/adc.2008.150219  4 Hutson J.M., et al. (2015) Cryptorchidism and Hypospadias. Endotext<a href="https://www.google.com/url?q=https://www.ncbi.nlm.nih.gov/books/NBK279106/&sa=D&ust=1554891396651000">https://www.ncbi.nlm.nih.gov/books/NBK279106/</a>  AOPWiki 2019-04-10T05:06:57

2019-04-10T05:27:42

<upstream-id>4c6db1c3-67f3-43bb-a1b5-8de98b375c5f</upstream-id> <downstream-id>fa969607-0de7-4aae-b9ea-1c1b33afe08f</downstream-id> <table> <tbody> <tr> <td colspan="1" rowspan="1">     </td> <td colspan="1" rowspan="1"> Cyp17a1 catalyzes the conversion of 17-OH-pregnenolone in DHEA through its 17α-hydroxylase activity. DHEA is synthesized by the cleavage of the c17,20 bond of 17-OH-pregnenolone. A lack in Cyp17a1’s activity directly affect this process resulting in a reduction in DHEA levels Cyp17a1 is found mainly found in Leydig cells and in the zona fasciculata/zona reticularis of the adrenal cortex.  123 </td> </tr> </tbody> </table>

The biological role of Cyp17a1 in 17-OH-pregnenolone/DHEA conversion is very well established. Cyp17a1 is known to cleave the c17,20bond of 10-OH-pregnenolone through its 17α-hydroxylase activity. 123

A major empirical evidence came from CYP17 knock down cell studies. In 2005, Liu Y., Yao ZX., and Papadopoulos V. showed that MA-10 CYP17 knock down cells synthesize much less pregnenolone and DHEA compared with MA-10 wild type cells. In this study, de novo endogenous cholesterol synthesis was blocked with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. After cells incubation with a radiolabeled cholesterol precursor ([3H]mevalonactone), progesterone and DHEA were fractionned using HPLC and identify using standards. After quantification by liquid scintillation spectrometry, results indicated that the MA-10CYP17KD cells synthesize much less pregnenolone, progesterone and DHEA. These results enable to highlight the important factor of CYP17a1 in 17-OH-pregnenolone conversion to DHEA. 4

The mentioned study is based on MA-10 mouse tumor Leydig cells. Even though mouse is the prefered animal model for reproductive studies, a human-cell based study would be stronger.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9f959c8> AOPWiki 2019-04-10T05:28:44

2019-04-10T05:31:29

<upstream-id>4c6db1c3-67f3-43bb-a1b5-8de98b375c5f</upstream-id> <downstream-id>cf3c680e-b2e4-4642-89e2-853fb65beba8</downstream-id> Cyp17a1 catalyzes the cleavage of c17,20 bond of 17-OH-progesterone to give androstenedione. This pathway is a direct conversion of DHEA by the enzyme 3β-hydroxysteroid dehydrogenase. A diminution in Cyp17a1 activity leads to a  reduction in both 17-OH-progesterone/androstenedione and DHEA/androstenedione conversion.  123

The biological role of Cyp17a1 in 17-OH-progesterone/androstenedione conversion is very well known. Most of androstenedione is synthesized through the 17,20-lyase activity of Cyp17a1. 123

Using MA-10 CYP17 knock down cells, Liu Y., Yao ZX., and Papadopoulos V. showed that cells without CYP17 enzyme tend to synthesize less progesterone than MA-10 wild type cells. For this particular study, endogenous cholesterol synthesis was blocked using 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. Cells were incubated with a radioactive cholesterol precursor to allow steroidogenesis monitoring. Newly-synthesized steroids were then collected, separated and identified using HPLC. After quantification by liquid scintillation spectrometry, results indicated that the MA-10CYP17KD cells synthesize much less progesterone than wild type cells. These results enable to highlight the important factor of CYP17a1 in 17-OH-progesterone conversion in androstenedione 4

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9fc8378> AOPWiki 2019-04-10T05:32:54

2019-04-10T05:35:35

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea0095d0> AOPWiki 2019-06-03T08:39:29

2019-06-03T08:39:29

<upstream-id>cf3c680e-b2e4-4642-89e2-853fb65beba8</upstream-id> <downstream-id>1f561ae6-6558-4226-82c2-b0078727dc84</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea044748> AOPWiki 2019-06-03T08:40:00

2019-06-03T08:40:00

<upstream-id>1f561ae6-6558-4226-82c2-b0078727dc84</upstream-id> <downstream-id>4df9849c-5ef3-444e-a2a8-296d8876371a</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea0810a8> AOPWiki 2019-06-03T08:40:16

2019-06-03T08:40:16

<upstream-id>4df9849c-5ef3-444e-a2a8-296d8876371a</upstream-id> <downstream-id>7fbe78fc-b6a8-4495-acf3-8909beff5e7b</downstream-id> Dihydrotestosterone (DHT) is, together with testosterone, a primary ligand for the Androgen receptor (AR). DHT is an endogenous sex hormone that is synthesis from e.g. testosterone  by the enzyme 5α-reductase in selected tissues, not least in the reproductive tracts of both sexes, but also other tissues and organs (<a href="#_ENREF_1" title="Davey, 2016 #250">Davey & Grossmann, 2016</a>; <a href="#_ENREF_3" title="Marks, 2004 #283">Marks, 2004</a>). In the absence of ligand (DHT/testosterone) the AR is localized in the cytoplasm. AR is only activated and translocated into the nucleus to carry out its ‘genomic function’ upon ligand binding (<a href="#_ENREF_1" title="Davey, 2016 #250">Davey & Grossmann, 2016</a>). Hence, AR transcriptional function is directly dependent on the presence of ligands, with DHT being a more potent AR activator (2-fold higher binding affinity) than testosterone (<a href="#_ENREF_2" title="Grino, 1990 #284">Grino et al, 1990</a>). Reduced levels of DHT will lead to reduced AR activation.

High Male

High

Foetal

High

During development and at adulthood

High High High High

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea1385c8> AOPWiki 2019-06-03T08:41:09

2021-02-02T05:50:18

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea15b078> AOPWiki 2019-06-03T08:41:23

2019-06-03T08:41:23

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea228cf8> AOPWiki 2019-06-03T08:41:52

2019-06-03T08:41:52

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea256630> AOPWiki 2019-06-03T08:42:05

2019-06-03T08:42:05

Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)

Cyp17A1 inhibition leads to undescended testes in mammals

Evgeniia Kazymova

Bérénice Collet; Bart van der Burg BioDetection Systems (Science Park 406,1098 XH Amsterdam - The Netherlands) Corresponding author: berenice.collet@bds.nl; bart.van.der.burg@bds.nl

BY-SA

2.0

This Adverse Outcome Pathway describes the linkage between a decrease in 7α-hydroxylase/C17,20-lyase (Cyp17a1) activity and a specific reproductive malformation in male newborns : impaired testicular descent also called cryptorchidism. Cyp17a1 enzyme is known to mediate 17 alpha-hydroxylase and 17,20-lyase activities, the distinction between the two being functional and not genetic or structural. Mainly expressed in Leydig cells, this steroidogenic enzyme catalyzes the conversion of 17-OH-pregnenolone and 17-OH-progesterone to dehydroepiandrosterone (DHEA) and androstenediol, respectively. In that way, a decrease in Cyp17a1 activity would inevitably lead to a decline in both steroid precursors’ levels. As a result, this succession of key events will affect testosterone (T) and dihydrotestosterone (DHT) synthesis and circulating levels. A direct consequence to such a drop in major androgens levels would be a decline in androgen receptor activation, causing potential disturbances in development and maintenance of the male reproductive system such as cryptorchidism. To understand this AOP, it is important to notice that the second stage of the testicular descent process called “inguinoscrotal“ is an androgen-dependent event that can be dramatically affected by variations in androgenic activity. The present AOP is linked to EU-ToxRisk Case Study 7: Read across evaluation of reproductive toxicity of conazoles. Conazoles are fungicide used in agriculture and as pharmaceuticals for treatment of human fungal diseases. They are known to act through inhibition of CYP51 which can be related to cross-reactivity with human enzymes involved in steroid metabolism, such as CYP17a1. In that respect, the proposed AOP and associated methods can be used as a basis to assess the effects of conazoles on steroidogenesis and reproductive development.

Abiraterone acetate used in androgen deprivation therapy4 , antifungals from the conazoles family5 (Ketonazole, Fadrozole, Imidazole, Prochloraz6…) etc.

adjacent

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High

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High

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High

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High

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High

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Moderate

Moderate adjacent

High

High Male

High

Development

Moderate Moderate

Life Stage Applicability This AOP is relevant for developing male. Sex Applicability This AOP applies to males only.

<table border="0" cellpadding="0" cellspacing="0" style="width:1107px"> <tbody> <tr> <td> </td> <td style="text-align:center">Key Events</td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td style="text-align:center">MIE</td> <td style="text-align:center">Inhibition, Cyp17a1</td> <td colspan="11">CYP17a1 has a decisive function in steroidogenesis by constituting the initial step in a series of biochemical reactions.</td> </tr> <tr> <td style="text-align:center">KE1</td> <td style="text-align:center">Reduction, DHEA conversion</td> <td colspan="11">17-OH-pregnenolone is the direct precursor of dehydroepiandrosterone (DHEA). (Miller et al., 1988 - 2011)</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">DHEA is the precursor of steroid hormones like testosterone and estradiol. </td> </tr> <tr> <td style="text-align:center">KE2</td> <td style="text-align:center">Reduction, Androstenedione conversion</td> <td colspan="11">17-OH-progesterone is the direct precursor of  androstenedione. (Miller et al., 1988; Liu et al., 2005)</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">Androstenedione is the precursor of steroid hormones like testosterone and estradiol.</td> </tr> <tr> <td style="text-align:center">KE3</td> <td style="text-align:center">Decrease, testosterone levels</td> <td colspan="11">Reduction in testosterone synthesis leads to a reduction in testosterone circulating levels. (Miller et al., 1988; Elder et al., 1985; Shiraishi et al., 2008)</td> </tr> <tr> <td style="text-align:center">KE4</td> <td style="text-align:center">Decrease, DHT levels</td> <td colspan="11">Reduction in DHT synthesis leads to a reduction in DHT circulating levels. (Miller et al., 1988 - 2011 1985; Shiraishi et al., 2008)</td> </tr> <tr> <td style="text-align:center">KE5</td> <td style="text-align:center">Decrease, AR activation</td> <td colspan="11">Androgen receptor activation is regulated by the binding of androgens. (Davey et al., 2016; Gao et al., 2005)</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">AR activity can be decreased by either a lack of steroidal ligands (testosterone, DHT) or the presence of an antagonist.</td> </tr> <tr> <td style="text-align:center">KE6</td> <td style="text-align:center">Impaired inguinoscrotal phase</td> <td colspan="11">Second phase of a two-step testis descent: the testis descends into the scrotum. (Hutson et al., 2015)</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">Any impairment in testis migration will directly result in the absence of one or both testes from the scrotum.</td> </tr> <tr> <td style="text-align:center">AOP</td> <td style="text-align:center">Malformation, cryptorchidism</td> <td colspan="11">Insertion of the testis in another position than the scrotum. (Hutson et al., 2015a - 2015b; Boisen et al., 2004; Acerini et al., 2009)</td> </tr> </tbody> </table>   <table border="0" cellpadding="0" cellspacing="0" style="width:1107px"> <tbody> <tr> <td> </td> <td>    </td> <td>How to measure</td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td style="text-align:center">MIE</td> <td> </td> <td colspan="11">Measurement in CYP17 MA-10 wild-type and CYP17 knock down MA-10 clone can be used to assess the effects of a dysfunction in CYP17a1 activity. (Liu et al., 2005)</td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td style="text-align:center">KE1</td> <td> </td> <td colspan="11">17-OH-pregnenolone and DHEA can be fractionated using High Performance Liquid Chromatography. After separation, pregnenolone and DHEA levels can be quantify using immunoassay such as ELISA or Radio Immuno Assay (RIA). For both steroids, LC-MS/MS is also an option.</td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td style="text-align:center">KE2</td> <td> </td> <td colspan="11"> Competitive immunoenzymatic colorimetric methods (ELISA) for quantitative determination of 17-OH-progesterone and androstenedione concentration in serum or plasma are available. Progesterone and androstenedione synthesis can be monitored using radiolabeled steroid precursor in association with High Performance Liquid Chromatography (HPLC). During synthesis, steroids will incorporate the radioactive label which can be afterwards, used for quantification. First of all, HPLC combined with internal standards can be used for steroids collection, fractionation and identification. Once separated from the other steroids, progesterone and androstenedione can be finally quantified using liquid scintillation spectrometry. </td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td style="text-align:center">KE3</td> <td> </td> <td colspan="11"> ELISA kit can be used for quantitative measurement of testosterone in various samples. Liquid Chromatography- tandem Mass Spectrometry is also an option. (Shiraishi et al., 2008) Detection of increase and decrease in the production of testosterone after chemical exposure can be measured using the validated H295R Steroidogenesis Assay associated with hormone measurement kits (ELISA) and/or instrumental techniques (LC-MS). (OECD, 2011) Testosterone (T) levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, testosterone can be identified by comparison with internal standards spectrum. Quantification of T levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling). </td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td style="text-align:center">KE4</td> <td> </td> <td colspan="11">DHT levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, DHT can be identify by comparison with internal standards spectrum. Quantification of DHT levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling). (Shiraishi et al., 2008)</td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td style="text-align:center">KE5</td> <td> </td> <td colspan="11"> Significance of AR signaling in fetal development can be studied through a conditional deletion of the androgen receptor using a Cre/loxP approach. The recommended animal model for reproductive study is the mouse. (Kaftanovskaya et al., 2012) Also, epidemiological case-studies following mouse or humans expressing a complete androgen insensitivity allow to directly assess the effects of a lack of AR activation on the development. (Hutson 1985) Enzyme immunoassay (ELISA) kits for in vitro quantitative measurement of AR activity are available. Androgen receptors activity can be measured using bioassay such as the (Anti-)Androgen Receptor CALUX reporter gene assay. (van der Burg et al., 2010) </td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td style="text-align:center">KE6</td> <td> </td> <td colspan="11">-</td> </tr> <tr> <td style="text-align:center"> </td> <td> </td> <td colspan="11"> </td> </tr> <tr> <td>AOP</td> <td> </td> <td colspan="11">Cryptorchidism is a birth defect that can be highlighted by a clinical examination. The aim of this palpation is to locate the gonad and determine its lowest position without causing painful traction on the spermatic cord. (Hutson et al., 2015)</td> </tr> </tbody> </table>

<table border="0" cellpadding="0" cellspacing="0" style="width:1057px"> <tbody> <tr> <td> </td> <td style="text-align:center">Key Event Relations</td> <td>General informations</td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td style="text-align:center"> </td> <td style="text-align:center"> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td style="text-align:center">KER1</td> <td style="text-align:center">Inhibition, Cyp17a1 - Reduction, DHEA conversion</td> <td colspan="11">Cyp17a1 catalyzes the conversion of 17-OH-pregnenolone in DHEA through its 17α-hydroxylase activity. </td> </tr> <tr> <td style="text-align:center">KER2</td> <td style="text-align:center">Inhibition, Cyp17a1 - Reduction, Androstenedione conversion</td> <td colspan="11">Cyp17a1 catalyzes the cleavage of c17,20 bond of 17-OH-progesterone to give androstenedione.</td> </tr> <tr> <td style="text-align:center">KER3</td> <td style="text-align:center">Reduction, DHEA/Androstenedione - Decrease, testosterone</td> <td colspan="11">Levels of two main testosterone precursors (DHEA and androstenedione) are decreased (KE1-KE2) </td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">Deficiency in these intermediate steroids directly lead to a reduction in testosterone synthesis.</td> </tr> <tr> <td style="text-align:center">KER4</td> <td style="text-align:center">Decrease, testosterone levels - Decrease, DHT levels</td> <td colspan="11">Testosterone being the precursor of DHT, a reduction in its synthesis/levels directly affects this metabolite.</td> </tr> <tr> <td style="text-align:center">KER5</td> <td style="text-align:center">Decrease, testosterone levels - Decrease, AR activation</td> <td colspan="11">A lack in androgenic hormones (either testosterone or DHEA) results in a diminution of AR activation.</td> </tr> <tr> <td style="text-align:center">KER6</td> <td style="text-align:center">Decrease, AR activation - Impaired inguinoscrotal phase</td> <td colspan="11">A dysfunction in androgens synthesis and AR activation leads to a defect in the inguinoscrotal stage.</td> </tr> <tr> <td style="text-align:center">AOP</td> <td style="text-align:center">Impaired inguinoscrotal phase - Malformation, cryptorchidism</td> <td colspan="11">A defect in the inguinoscrotal stage leads to an impairment in the testis descent to the scrotum. </td> </tr> </tbody> </table>   <table border="0" cellpadding="0" cellspacing="0" style="width:1498px"> <tbody> <tr> <td> </td> <td style="text-align:center">Key Event Relations</td> <td colspan="12">Biological plausibility</td> </tr> <tr> <td style="text-align:center">KER1</td> <td style="text-align:center">Inhibition, Cyp17a1 - Reduction, DHEA conversion</td> <td style="text-align:center">High</td> <td colspan="11">Cyp17a1 is known to cleave the c17,20bond of 10-OH-pregnenolone through its 17α-hydroxylase activity.</td> </tr> <tr> <td style="text-align:center">KER2</td> <td style="text-align:center">Inhibition, Cyp17a1 - Reduction, Androstenedione conversion</td> <td style="text-align:center">High</td> <td colspan="11">Most of androstenedione is synthesized through the 17,20-lyase activity of Cyp17a1.</td> </tr> <tr> <td style="text-align:center">KER3</td> <td style="text-align:center">Reduction, DHEA/Androstenedione - Decrease, testosterone</td> <td style="text-align:center">High</td> <td colspan="11">This steroid can be synthesized from either  DHEA/Androstenediol or Androstenedione both catalyzed by the 3β-hydroxysteroid dehydrogenase enzyme.</td> </tr> <tr> <td style="text-align:center">KER4</td> <td style="text-align:center">Decrease, testosterone levels - Decrease, DHT levels</td> <td style="text-align:center">High</td> <td colspan="11">Testosterone is converted to DHT by 5alpha-reductase.</td> </tr> <tr> <td style="text-align:center">KER5</td> <td style="text-align:center">Decrease, testosterone levels - Decrease, AR activation</td> <td style="text-align:center">High</td> <td colspan="11">AR is a ligand-dependent nuclear transcription factor. Its activation is known to be mediated by Testosterone and DHT.</td> </tr> <tr> <td style="text-align:center">KER6</td> <td style="text-align:center">Decrease, AR activation - Impaired inguinoscrotal phase</td> <td style="text-align:center">Moderate</td> <td colspan="11">Although causes of cryptorchidism are not well-established, androgens are known to play an important role in the inguinoscrotal testicular descent</td> </tr> <tr> <td style="text-align:center">KER6</td> <td style="text-align:center">Decrease, AR activation - Impaired inguinoscrotal phase</td> <td> </td> <td colspan="11">in both animals and humans. Variation affecting androgens levels and AR activation directly lead to defect in the inguinoscrotal phase of testis descent. </td> </tr> <tr> <td style="text-align:center">AOP</td> <td style="text-align:center">Impaired inguinoscrotal phase - Malformation, cryptorchidism</td> <td style="text-align:center">High</td> <td colspan="11">Any impairment affecting thie inguinoscrotal phase has direct repercussion on proper testis descent.</td> </tr> </tbody> </table>   <table border="0" cellpadding="0" cellspacing="0" style="width:1181px"> <tbody> <tr> <td style="text-align:center"> </td> <td>  </td> <td colspan="11">Empirical support</td> </tr> <tr> <td style="text-align:center">KER1</td> <td> </td> <td colspan="11">In 2005, Liu Y., Yao ZX., and Papadopoulos V. showed that MA-10 CYP17 knock down cells synthesize much  less </td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">pregnenolone and DHEA compared with MA-10 wild type cells.</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"><a href="https://doi.org/10.1210/me.2004-0271">https://doi.org/10.1210/me.2004-0271 </a></td> </tr> <tr> <td style="text-align:center">KER2</td> <td> </td> <td colspan="11">Using MA-10 CYP17 knock down cells, Liu Y., Yao ZX., and Papadopoulos V. showed that cells without CYP17 enzyme</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"> tend to synthesize less progesterone than MA-10 wild type cells.</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"><a href="https://doi.org/10.1210/me.2004-0271">https://doi.org/10.1210/me.2004-0271 </a></td> </tr> <tr> <td style="text-align:center">KER3</td> <td> </td> <td colspan="11">-</td> </tr> <tr> <td style="text-align:center">KER4</td> <td> </td> <td colspan="11">An enzyme immunoassay such as ELISA kit can be used for quantitative determination of DHT levels.</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">The ratio of serum testosterone to serum DHT shows the general activity of 5-alpha reductase.</td> </tr> <tr> <td style="text-align:center">KER5</td> <td> </td> <td colspan="11">Norris J.D., et al. highlighted that CYP17 inhibition using lyase–selective inhibitor antagonize AR activation.</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"><a href="https://doi.org/10.1172/JCI87328">https://doi.org/10.1172/JCI87328 </a></td> </tr> <tr> <td style="text-align:center">KER6</td> <td> </td> <td colspan="11">In 1985, Hutson studied both mice model and humans expressing a complete androgen insensitivity. This particular</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">research demonstrated that in such case, the testis remains in the inguinal canal or groin.</td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"><a href="http://dx.doi.org/10.1016/S0140-6736(85)92739-4">http://dx.doi.org/10.1016/S0140-6736(85)92739-4 </a></td> </tr> <tr> <td> </td> <td> </td> <td colspan="9">Kaftanovskaya et al. confirmed the previous statement in 2012 using a Cre-loxP approach study</td> <td> </td> <td> </td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"><a href="https://doi.org/10.1210/me.2011-1283">https://doi.org/10.1210/me.2011-1283 </a></td> </tr> <tr> <td style="text-align:center">AOP</td> <td> </td> <td colspan="11">Kaftanovskaya et al. research are based on conditional deletion of the androgen receptor using a Cre/loxP approach in male mice. </td> </tr> <tr> <td> </td> <td> </td> <td colspan="11">Study from 2012 showed that a depletion of the AR in the gubernaculum leads to an impairment in inguinoscrotal phase and induces cryptorchidism. </td> </tr> <tr> <td> </td> <td> </td> <td colspan="11"><a href="https://doi.org/10.1210/me.2011-1283">https://doi.org/10.1210/me.2011-1283 </a></td> </tr> </tbody> </table>

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