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Title page
Contents
Foreword 3
Abstract 7
Graphical Representation 8
Summary of the AOP 9
Molecular Initiating Events (MIEs), Key Events (KEs), Adverse Outcomes (AOs) 9
Key Event Relationships (KERs) 9
Stressors 10
17beta-Trenbolone 10
Overall Assessment of the AOP 11
Domain of Applicability 11
Life Stage Applicability 11
Taxonomic Applicability 11
Sex Applicability 11
Essentiality of the Key Events 12
Weight of Evidence Summary 12
Quantitative Consideration 15
References 16
Appendix 1: List of MIE(s), KE(s) and AO(s) in the AOP 24
List of MIE(s) in this AOP 24
Event: 25: Agonism, Androgen receptor 24
List of KE(s) in the AOP 31
Event: 129: Reduction, Gonadotropins, circulating concentrations 31
Event: 274: Reduction, Testosterone synthesis by ovarian theca cells 34
Event: 3: Reduction, 17beta-estradiol synthesis by ovarian granulosa cells 37
Event: 219: Reduction, Plasma 17beta-estradiol concentrations 40
Event: 285: Reduction, Vitellogenin synthesis in liver 43
Event: 221: Reduction, Plasma vitellogenin concentrations 46
Event: 309: Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development 48
Event: 78: Reduction, Cumulative fecundity and spawning 50
List of AO(s) in this AOP 52
Event: 360: Decrease, Population trajectory 52
Appendix 2: List of Key Event Relationships in the AOP 54
List of Adjacent Key Event Relationships 54
Relationship: 31: Agonism, Androgen receptor leads to Reduction, Gonadotropins, circulating concentrations 54
Relationship: 143: Reduction, Gonadotropins, circulating concentrations leads to Reduction, Testosterone synthesis by ovarian theca cells 57
Relationship: 302: Reduction, Testosterone synthesis by ovarian theca cells leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells 59
Relationship: 5: Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations 63
Relationship: 252: Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Vitellogenin synthesis in liver 68
Relationship: 315: Reduction, Vitellogenin synthesis in liver leads to Reduction, Plasma vitellogenin concentrations 72
Relationship: 255: Reduction, Plasma vitellogenin concentrations leads to Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development 75
Relationship: 337: Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development leads to Reduction, Cumulative fecundity and spawning 78
Relationship: 94: Reduction, Cumulative fecundity and spawning leads to Decrease, Population trajectory 81
List of Non Adjacent Key Event Relationships 84
Relationship: 32: Agonism, Androgen receptor leads to Reduction, Testosterone synthesis by ovarian theca cells 84
Relationship: 1384: Agonism, Androgen receptor leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells 89
Relationship: 1385: Agonism, Androgen receptor leads to Reduction, Vitellogenin synthesis in liver 92
Relationship: 1386: Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations 96
Appendix 3: Concordance Table 101
Table 1. Summary of the experimental data for decrease E2 production and decreased E2 levels. IC50- half maximal inhibitory concentration values reported if available, otherwise the concentration... 65
Figure 1. Overview of steroid biosynthesis pathway. Note, testosterone is converted to 17ß-estradiol through aromatization catalyzed by cyp19 (aromatase) 60
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