Classifying chemical mode of action using gene networks and machine learning: A case study with the herbicide linuron

Comparative Biochemistry and Physiology - Part D: Genomics and Proteomics

Volumn 8, Issue 4, 2013, Pages 263-274

  Ornostay, Anna ^a   Cowie, Andrew M ^a   Hindle, Matthew ^b   Baker, Christopher J O ^b   Martyniuk, Christopher J ^a  

^a UNIVERSITY OF NEW BRUNSWICK   (Canada)

^b UNIVERSITY OF NEW BRUNSWICK   (Canada)

Author keywords

Machine learning Sub network enrichment analysis Wnt frizzled pathway Herbicides Notch signaling

Indexed keywords

ANDROGEN; ANDROGEN RECEPTOR; ANDROSTANOLONE; ANTIANDROGEN; DNA; ESTRADIOL; FLUTAMIDE; LINURON; STEROID;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CASE STUDY; CONTROLLED STUDY; DNA REPLICATION; DRUG EFFECT; DRUG MECHANISM; EXPLANT; FEMALE; FISH; GENE EXPRESSION; GENE REGULATORY NETWORK; GENETIC ALGORITHM; IN VITRO STUDY; IN VIVO STUDY; MACHINE LEARNING; NONHUMAN; NUCLEOTIDE SEQUENCE; OVARY; OVARY EXPLANT; PIMEPHALES PROMELAS; PRIORITY JOURNAL; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; STEROID METABOLISM; TELEOST; TRANSCRIPTOMICS; TRANSLATION REGULATION; VITELLOGENESIS;

PIMEPHALES PROMELAS;

17-Β ESTRADIOL; 17BETA-TRENBOLONE; 24-DEHYDROCHOLESTEROL REDUCTASE; 5Α-DIHYDROTESTOSTERONE; ANDROGEN RECEPTOR; AR; AXIN 1; AXIN1; BCL2-LIKE 1; BCL2L1; BMPR; BONE MORPHOGENETIC PROTEIN RECEPTOR; C; CASEIN KINASE 1, EPSILON; CATENIN (CADHERIN-ASSOCIATED PROTEIN), BETA 1, 88KDA; CSNK1E; CTNNB1; CYP17A1; CYP1B1; CYTOCHROME P450, FAMILY 1, SUBFAMILY B, POLYPEPTIDE 1; CYTOCHROME P450, FAMILY 17, SUBFAMILY A, POLYPEPTIDE 1; DHCR24; DHT; DISHEVELED, DSH HOMOLOG 1 (DROSOPHILA); DVL1; E(2); EDCS; ENDOCRINE DISRUPTING COMPOUNDS; ER; ESTROGEN RECEPTOR; FABP1; FATHEAD MINNOW; FATTY ACID BINDING PROTEIN 1, LIVER; FDX1; FERREDOXIN 1; FGF8; FHM; FIBROBLAST GROWTH FACTOR 8 (ANDROGEN-INDUCED); FIBRONECTIN 1; FLUT; FLUTAMIDE; FN1; FOLLICLE STIMULATING HORMONE, BETA POLYPEPTIDE; FORKHEAD BOX O3; FOS; FOXO; FRAT1; FREQUENTLY REARRANGED IN ADVANCED T-CELL LYMPHOMAS; FRIZZLED RECEPTOR; FSHB; FZD; GENE ONTOLOGY; GENE SET ENRICHMENT ANALYSIS; GH1; GLYCOGEN SYNTHASE KINASE 3 BETA; GNRH; GO; GONADOTROPIN-RELEASING HORMONE RECEPTOR; GROWTH HORMONE 1; GSEA; GSK3B; HERBICIDES; HNF1 HOMEOBOX B; HNF1B; ID1; IFT88; IL16; INHIBITOR OF DNA BINDING 1, DOMINANT NEGATIVE HELIX-LOOP-HELIX PROTEIN; INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 145KDA; INPP5D; INTERLEUKIN 16 (LYMPHOCYTE CHEMOATTRACTANT FACTOR); INTRAFLAGELLAR TRANSPORT 88 HOMOLOG (CHLAMYDOMONAS); JUN; JUN ONCOGENE; LDLR; LEFT-RIGHT DETERMINATION FACTOR 2; LEFTY2; LIN; LINURON; LOW DENSITY LIPOPROTEIN RECEPTOR; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 6; LRP6; MACHINE LEARNING; MATRIX METALLOPEPTIDASE 9 (GELATINASE B,92KDA GELATINASE,92KDA TYPE IV COLLAGENASE); MMP9; MOA; MODE OF ACTION; MYC; NOTCH SIGNALING; NUCB2; NUCLEOBINDIN 2; PARAMETER OF COST; PCK2; PCR; PCSK2; PHOSPHOENOLPYRUVATE CARBOXYKINASE 2 (MITOCHONDRIAL); POLYMERASE CHAIN REACTION; POMC; PROOPIOMELANOCORTIN; PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 2; RADIAL BASIS MACHINE; RBM; SEMA DOMAIN, IMMUNOGLOBULIN DOMAIN (IG), SHORT BASIC DOMAIN, SECRETED, (SEMAPHORIN) 3A; SEMA3A; SEX HORMONE-BINDING GLOBULIN; SHBG; SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION; SLC5A1; SNEA; SOCS3; SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE COTRANSPORTER), MEMBER 1; STAT; SUB-NETWORK ENRICHMENT ANALYSIS; SUPPORT VECTOR MACHINE; SUPPRESSOR OF CYTOKINE SIGNALING 3; SVM; TB; TFE3; TGFBR; TH; TRANSCRIPTION FACTOR BINDING TO IGHM ENHANCER 3; TRANSFORMING GROWTH FACTOR, BETA RECEPTOR 1; TYROSINE HYDROXYLASE; V-FOS FBJ MURINE OSTEOSARCOMA VIRAL ONCOGENE HOMOLOG; V-MYC MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG (AVIAN); VITELLOGENIN; VTG; WNT-FRIZZLED PATHWAY;

ANDROGEN ANTAGONISTS; ANIMALS; ARTIFICIAL INTELLIGENCE; CYPRINIDAE; DIHYDROTESTOSTERONE; ENDOCRINE DISRUPTORS; ESTRADIOL; FEMALE; FLUTAMIDE; GENE EXPRESSION PROFILING; GENE REGULATORY NETWORKS; LINURON; OVARY; RECEPTORS, ANDROGEN; SIGNAL TRANSDUCTION; SUPPORT VECTOR MACHINES; WATER POLLUTANTS, CHEMICAL;

EID: 84883571256     PISSN: 1744117X     EISSN: 18780407     Source Type: Journal    
DOI: 10.1016/j.cbd.2013.08.001     Document Type: Article

References (68)

1. G.T. Ankley, and D.L. Villeneuve The fathead minnow in aquatic toxicology: past, present and future Aquat. Toxicol. 78 2006 91 102 (Pubitemid 43668713)
2. G.T. Ankley, K.M. Jensen, E.A. Makynen, M.D. Kahl, J.J. Korte, M.W. Hornung, T.R. Henry, J.S. Denny, R.L. Leino, V.S. Wilson, M.C. Cardon, P.C. Hartig, and L.E. Gray Effects of the androgenic growth promoter 17-beta-trenbolone on fecundity and reproductive endocrinology of the fathead minnow Environ. Toxicol. Chem. 22 2003 1350 1360 (Pubitemid 37092491)
3. D. Baron, J. Montfort, R. Houlgatte, A. Fostier, and Y. Guiguen Androgen-induced masculinization in rainbow trout results in a marked dysregulation of early gonadal gene expression profiles BMC Genomics 8 2007 1 18
4. A. Boyer, K.A. Goff, and D. Boerboom WNT signaling in ovarian follicle biology and tumorigenesis Trends Endocrinol. Metab. 21 2010 2532
5. P.Y. Caux, A.R. Kent, T.G. Fan, and C. Grande Canadian water quality guidelines for linuron Environ. Toxicol. Water 13 1998 1 41 (Pubitemid 28056756)
6. S. Chakrabarty, A. Rajakumar, K. Raghuveer, P. Sridevi, A. Mohanachary, Y. Prathibha, L. Bashyam, A. Dutta-Gupta, and B. Senthilkumaran Endosulfan and flutamide, alone and in combination, target ovarian growth in juvenile catfish, Clarias batrachus Comp. Biochem. Physiol. C 155 2012 491 497
7. J. Crago, and R. Klaper A mixture of an environmentally realistic concentration of a phthalate and herbicide reduces testosterone in male fathead minnow (Pimephales promelas) through a novel mechanism of action Aquat. Toxicol. 110 2012 74 83
8. S.I. Da'as, A.J. Coombs, T.B. Balci, C.A. Grondin, A.A. Ferrando, and J.N. Berman The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo Blood 119 2012 3585 3594
9. A. Daxenberger Pollutants with androgen-disrupting potency Eur. J. Lipid Sci. Technol. 104 2002 124 130 (Pubitemid 34848698)
10. J. Dorts, C.A. Richter, M.K. Wright-Osment, M.R. Ellersieck, B.J. Carter, and D.E. Tillitt The genomic transcriptional response of female fathead minnows (Pimephales promelas) to an acute exposure to the androgen, 17 beta-trenbolone Aquat. Toxicol. 91 2009 44 53
11. K.L. Forsgren, and G. Young Stage-specific effects of androgens and estradiol-17beta on the development of late primary and early secondary ovarian follicles of coho salmon (Oncorhynchus kisutch) in vitro Biol. Reprod. 87 3 2012 64
12. T.S. Furey, N. Cristianini, N. Duffy, D.W. Bednarski, M. Schummer, and D. Haussler Support vector machine classification and validation of cancer tissue samples using microarray expression data Bioinformatics 16 2000 906 914
13. N. Garcia-Reyero, D.L. Villeneuve, K.J. Kroll, L. Liu, E.F. Orlando, K.H. Watanabe, M.S. Sepúlveda, G.T. Ankley, and N.D. Denslow Expression signatures for a model androgen and anti-androgen in the fathead minnow (Pimephales promelas) ovary Environ. Sci. Technol. 43 2009 2614 2619
14. T.R. Golub, D.K. Slonim, P. Tamayo, C. Huard, M. Gaasenbeek, J.P. Mesirov, H. Coller, M.L. Loh, J.R. Downing, M.A. Caligiuri, C.D. Bloomfield, and E.S. Lander Molecular classification of cancer: class discovery and class prediction by gene expression monitoring Science 286 1999 531 535
15. I. Guyon, J. Weston, S. Barnhill, and V. Vapnik Gene selection for cancer classification using support vector machines Mach. Learn. 46 2002 389 422 (Pubitemid 34129977)
16. T. Hayashi, Y. Kageyama, K. Ishizaka, G. Xia, K. Kihara, and H. Ashima Requirement of Notch 1 and its ligand jagged 2 expressions for spermatogenesis in rat and human testes J. Androl. 22 2001 999 1011 (Pubitemid 33020322)
17. J.L. Hoffmann, R.G. Thomason, D.M. Lee, J.L. Brill, B.B. Price, G.L. Carr, and D.J. Versteeg Hepatic gene expression profiling using GeneChips in zebrafish exposed to 17 alpha-methyldihydrotestosterone Aquat. Toxicol. 87 2008 69 80
18. N.S. Hogan, M.J. Gallant, and M.R. van den Heuvel Exposure to the pesticide linuron affects androgen-dependent gene expression in the three-spined stickleback (Gasterosteus aculeatus) Environ. Toxicol. Chem. 31 2012 1391 1395
19. C.W. Hsu, C.C. Chang, and C.J. Lin A Practical Guide to Support Vector Classification 2010 Department of Computer Science, National Taiwan University Taipei, Taiwan (Software available at (http://www.csie.ntu.edu.tw/~cjlin/cgi- bin/libsvm.cgi?+http://www.csie.ntu.edu.tw/~cjlin/libsvm+zip)
20. Y.S. Huang, Y.M. Chen, P.C. Liao, Y.H. Lee, J.C. Gwo, M.C. Chen, and C.F. Chang Testosterone improves the transition of primary oocytes in artificial maturation eels (Anguilla japonica) by altering ovarian PTEN expression Fish Physiol. Biochem. 38 2012 777 787
21. K.M. Jensen, J.J. Korte, M.D. Kahl, M.S. Pasha, and G.T. Ankley Aspects of basic reproductive biology and endocrinology in the fathead minnow (Pimephales promelas) Comp. Biochem. Physiol. C 128 2001 127 141
22. K.M. Jensen, M.D. Kahl, E.A. Makynen, J.J. Korte, R.L. Leino, B.C. Butterworth, and G.T. Ankley Characterization of responses to the antiandrogen flutamide in a short-term reproduction assay with the fathead minnow Aquat. Toxicol. 70 2004 99 110 (Pubitemid 39441286)
23. S. Jobling, R.W. Burn, K. Thorpe, R. Williams, and C. Tyler Statistical modeling suggests that antiandrogens in effluents from wastewater treatment works contribute to widespread sexual disruption in fish living in English rivers Environ. Health Perspect. 117 2009 797 802
24. C. Jolly, I. Katsiadaki, S. Morris, N. Le Belle, S. Dufour, I. Mayer, T.G. Pottinger, and A.P. Scott Detection of anti-androgenic effect of endocrine disrupting environmental contaminants using in vivo and in vitro assays in the three-spined stickleback Aquat. Toxicol. 92 2009 228 239
25. I. Katsiadaki, S. Morris, C. Squires, M.R. Hurst, J.D. James, and A.P. Scott Use of the three-spined stickleback (Gasterosteus aculeatus) as a sensitive in vivo test for detection of environmental antiandrogens Environ. Health Perspect. 114 2006 115 121
26. B. Kim, A. Takemura, J.S. Kim, and Y.D. Lee Vitellogenin synthesis via androgens in primary cultures of tilapia hepatocytes Gen. Comp. Endocrinol. 132 2003 248 255 (Pubitemid 36694059)
27. T.M. Kortner, E. Rocha, P. Silva, L.F. Castro, and A. Arukwe Genomic approach in evaluating the role of androgens on the growth of Atlantic cod (Gadus morhua) previtellogenic oocytes Comp. Biochem. Physiol. D 3 2008 205 218
28. V.S. Langlois, and C.J. Martyniuk Genome wide analysis of Silurana (Xenopus) tropicalis development reveals dynamic expression using network enrichment analysis Mech. Dev. 130 4-5 2013 304 322
29. J.F. Leatherland, M. Li, and S. Barkataki Stressors, glucocorticoids and ovarian function in teleosts J. Fish Biol. 76 2010 86 111
30. R.L. Leino, K.M. Jensen, and G.T. Ankley Gonadal histology and characteristic histopathology associated with endocrine disruption in the fathead minnow (Pimephales promelas) Environ. Toxicol. Pharmacol. 19 2005 85 98 (Pubitemid 39601905)
31. F. Lemenn, H. Rochefort, and M. Garcia Effect of androgen mediated by the estrogen-receptor of fish liver - vitellogenin accumulation Steroids 35 1980 315 328 (Pubitemid 10125214)
32. J.A. Luckenbach, D.B. Iliev, F.W. Goetz, and P. Swanson Identification of differentially expressed ovarian genes during primary and early secondary oocyte growth in coho salmon, Oncorhynchus kisutch Reprod. Biol. Endocrinol. 6 2 2008 (18)
33. L. Marigotta-Casaluci, and J.P. Sumpter 5α-Dihydrotestosterone is a potent androgen in the fathead minnow (Pimephales promelas) Gen. Comp. Endocrinol. 171 2011 309 318
34. V.L. Marlatt, B.P. Lo, A. Ornostay, N.S. Hogan, C.J. Kennedy, J.R. Elphick, and C.J. Martyniuk The effects of the ureic-based herbicide linuron on reproductive endpoints in the fathead minnow (Pimephales promelas) Comp. Biochem. Physiol. C 157 2013 24 32
35. D. Martinović-Weigelt, R.L. Wang, D.L. Villeneuve, D.C. Bencic, J. Lazorchak, and G.T. Ankley Gene expression profiling of the androgen receptor antagonists flutamide and vinclozolin in zebrafish (Danio rerio) gonads Aquat. Toxicol. 101 2011 447 458
36. C.J. Martyniuk, and N.D. Denslow Exploring androgen-regulated pathways in teleost fish using transcriptomics and proteomics Integr. Comp. Biol. 52 2012 695 704
37. C.J. Martyniuk, S. Alvarez, S. McClung, D.L. Villeneuve, G.T. Ankley, and N.D. Denslow Quantitative proteomic profiles of androgen receptor signaling in the liver of fathead minnows (Pimephales promelas) J. Proteome Res. 8 2009 2186 2200
38. C.J. Martyniuk, M.S. Prucha, N.J. Doperalski, P. Antczak, K.J. Kroll, F. Falciani, D.S. Barber, and N.D. Denslow Gene expression networks underlying ovarian development in wild largemouth bass (Micropterus salmoides) PLoS One 8 3 2013 e59093
39. C.J. Martyniuk, N.J. Doperalski, K.J. Kroll, D.S. Barber, and N.D. Denslow Sexually dimorphic transcriptomic responses in the teleostean hypothalamus: a case study with the organochlorine pesticide dieldrin Neurotoxicology 34C 2013 105 117
40. S. Nadarajan, J.A. Govindan, and M. McGovern MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth in C. elegans Development 136 2009 2223 2234
41. B. Nicol, and Y. Guiguen Expression profiling of Wnt signaling genes during gonadal differentiation and gametogenesis in rainbow trout Sex. Dev. 5 2011 318 329
42. A. Nikitin, S. Egorov, N. Daraselia, and I. Mazo Pathway studio - the analysis and navigation of molecular networks Bioinformatics 19 16 2003 2155 2157 (Pubitemid 37408171)
43. N. Ninov, M. Borius, and D.Y.R. Stainier Different levels of Notch signaling regulate quiescence, renewal and differentiation in pancreatic endocrine progenitors Development 139 2012 1557 1567
44. W.S. Noble What is a support vector machine? Nat. Biotechnol. 24 12 2006 1565 1567 (Pubitemid 44967481)
45. G.H. Panter, T.H. Hutchinson, K.S. Hurd, A. Sherren, R.D. Stanley, and C.R. Tyler Successful detection of (anti-) androgenic and aromatase inhibitors in pre-spawning adult fathead minnows (Pimephales promelas) using easily measured endpoints of sexual development Aquat. Toxicol. 70 2004 11 21 (Pubitemid 39296969)
46. J.L. Parrott, and B.R. Blunt Life-cycle exposure of fathead minnows (Pimephales promelas) to an ethinylestradiol concentration below 1 ng/L reduces egg fertilization success and demasculinizes males Environ. Toxicol. 20 2005 131 141
47. S. Payam, R.M. Seethammagari, M.J. Valdez, L. Xin, and M.D. Spencer Wnt and Notch pathways have interrelated opposing roles on prostate progenitor cell proliferation and differentiation Stem Cells 29 2011 678 688
48. E.J. Perkins, K.J. Chipman, S. Edwards, T. Habib, F. Falciani, R. Taylor, G. Van Aggelen, C. Vulpe, P. Antczak, and A. Loguinov Reverse engineering adverse outcome pathways Environ. Toxicol. Chem. 30 2011 22 38
49. L. Pireddu, L. Michielan, M. Floris, P. Rodriquez-Tome, and S. Moro Fingerprint-based detection of acute aquatic toxicity J. Chem. Inf. 2 Suppl. 1 2010 46
50. A. Rajakumar, R. Singh, S. Chakrabarty, R. Murugananthkumar, C. Laldinsangi, Y. Prathibha, C.C. Sudhakumari, A. Dutta-Gupta, and B. Senthilkumaran Endosulfan and flutamide impair testicular development in the juvenile Asian catfish, Clarias batrachus Aquat. Toxicol. 110-111 2012 123 132
51. 2 Chem. Eng. J. 158 2010 181 187
52. S. Rozen, and H. Skaletsky Primer3 on the WWW for general users and for biologist programmers Methods Mol. Biol. 132 2000 365 386
53. A.D. Shilling, and D.E. Williams The non-aromatizable androgen, dihydrotestosterone, induces antiestrogenic responses in the rainbow trout J. Steroid Biochem. 74 2000 187 194 (Pubitemid 32121654)
54. J. Struger, J. Grabuski, S. Cagampan, M. Rondeau, E. Sverko, and C. Marvin Occurrence and distribution of sulfonylurea and related herbicides in central Canadian surface waters 2006-2008 Environ. Contam. Toxicol. 87 2011 420 425
55. A. Subramanian, P. Tamayo, V.K. Mootha, S. Mukherjee, B.L. Ebert, M.A. Gillette, A. Paulovich, S.L. Pomeroy, T.R. Golub, E.S. Lander, and J.P. Mesirov Gene set enrichment analysis: a knowledge-based approach for interpreting genome wide expression profiles PNAS 102 43 2005 15545 15550 (Pubitemid 41528093)
56. H. Tang, J. Brennan, J. Karl, Y. Hamada, L. Raetzman, and B. Capel Notch signaling maintains Leydig progenitor cells in the mouse testis Development 135 2008 3745 3753
57. S. Taylor, M. Wakem, G. Dijkman, M. Alsarraj, and M. Nguyen A practical approach to RT-qPCR - publishing data that conform to the MIQE guidelines Methods 50 2010 1 5
58. G. Tsoumakas, and I. Katakis Multi-label classification: an overview IJDWM 3 3 2007 1 13
59. R.L. Wang, D. Bencic, A. Biales, D. Lattier, M. Kostich, D. Villeneuve, G.T. Ankley, J. Lazorchak, and G. Toth DNA microarray-based ecotoxicological biomarker discovery in a small fish model species Environ. Toxicol. Chem. 27 2008 664 675 (Pubitemid 351413535)
60. R. Wang, Y. Gao, L. Zhang, Y. Zhang, Z. Fang, J. He, W. Zhang, and G. Ma Cloning, expression, and induction by 17-beta estradiol (E2) of a vitellogenin gene in the white cloud mountain minnow Tanichthys albonubes Fish Physiol. Biochem. 36 2010 157 164
61. R.L. Wang, D. Bencic, A. Biales, R. Flick, J. Lazorchak, D. Villeneuve, and G.T. Ankley Discovery and validation of gene classifiers for endocrine-disrupting chemicals in zebrafish (Danio rerio) BMC Genomics 13 2012 358
62. V.S. Wilson, C.M. Cardon, L.E. Gray Jr., and P.C. Hartig Competitive binding comparison of endocrine-disrupting compounds to recombinant androgen receptor from fathead minnow, rainbow trout, and human Environ. Toxicol. Chem. 26 2007 1793 1802 (Pubitemid 47373192)
63. V.S. Wilson, C.R. Lambright, J.R. Furr, K.L. Howdeshell, and L.E. Gray Jr. The herbicide linuron reduces testosterone production from the fetal rat testis during both in utero and in vitro exposures Toxicol. Lett. 186 2009 73 77
64. B.M. Woudneh, Z. Ou, M. Sekela, T. Tuominen, and M. Gledhill Pesticide multiresidues in water of the Lower Fraser Valley, British Columbia, Canada. Part I. Surface water J. Environ. Qual. 38 1998 948 954
65. G.C. Wu, and C.F. Chang Wnt4 is associated with the development of ovarian tissue in the protandrous black porgy, Acanthopagrus schlegeli Biol. Reprod. 81 2009 1073 1082
66. C. Yuan, Y. Zhang, G. Hu, M. Li, Y. Zheng, J. Gao, Y. Yang, Y. Zhou, and Z. Wang Expression of two zona pellucida genes is regulated by 17α-ethinylestradiol in adult rare minnow Gobiocypris rarus Comp. Biochem. Physiol. C Toxicol. Pharmacol. 158 1 2013 Jun 1 9
67. X. Zhang, M. Hecker, J.W. Park, A.R. Tompsett, P.D. Jones, J. Newsted, D.W. Au, R. Kong, R.S. Wu, and J.P. Giesy Time-dependent transcriptional profiles of genes of the hypothalamic-pituitary-gonadal axis in medaka (Oryzias latipes) exposed to fadrozole and 17beta-trenbolone Environ. Toxicol. Chem. 27 12 2008 2504 2511
68. C.P. Zhang, J.L. Yang, J. Zhang, L. Huang, S.Y. Ji, Z.Y. Hu, F. Gao, and Y.X. Liu Notch signaling is involved in ovarian follicle development by regulating granulosa cell proliferation Endocrinology 152 2011 2437 2447