DART AOPs

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AOP Collection · Submitted · Created by Clemens Wittwehr (send email) · Contributors: Clemens Wittwehr, Lidwina Gerner

Purpose
A collection of Adverse Outcome Pathways (AOPs) relevant to Developmental and Reproductive Toxicity (DART). It was initiated following the ISTNET-DART Workshop held in Basel on 24–25 September 2026. This is a first, evolving collection and is open to discussion, review and further refinement.
Creation Strategy
Candidate AOPs were identified through two complementary routes: a semantic screening of the AOP-Wiki using the expert-defined DART scope, and a reviewed ontology-term-based analysis. The combined candidate set was then provisionally assessed for DART strength. This collection includes all AOPs classified as C1, meaning that developmental or reproductive biology is considered the principal causal focus of the pathway. No restriction was applied based on OECD status; endorsed, under-review and other AOPs were included equally.
Creation Strategy Notes

Candidate AOPs were identified through two complementary routes: a semantic screening of the AOP-Wiki using the expert-defined DART scope, and a reviewed ontology-term-based analysis. The combined candidate set was then provisionally assessed for DART strength.

This collection includes all AOPs classified as C1, meaning that developmental or reproductive biology is considered the principal causal focus of the pathway. No restriction was applied based on OECD status; endorsed, under-review and other AOPs were included equally.

AOPs in this Collection (88)

ID Title License OECD Status
7 Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female BY-SA Under Review
8 Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Open for adoption Under Development
12 Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging BY-SA WPHA/WNT Endorsed
13 Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities BY-SA WPHA/WNT Endorsed
15 Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations BY-SA WPHA/WNT Endorsed
17 Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory BY-SA WPHA/WNT Endorsed
18 PPARα activation in utero leading to impaired fertility in males BY-SA Under Review
23 Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish) BY-SA WPHA/WNT Endorsed
25 Aromatase inhibition leading to reproductive dysfunction BY-SA WPHA/WNT Endorsed
28 Cyclooxygenase inhibition leading reproductive failure BY-SA
29 Estrogen receptor agonism leading to reproductive dysfunction BY-SA
30 Estrogen receptor antagonism leading to reproductive dysfunction BY-SA Under Review
42 Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals BY-SA WPHA/WNT Endorsed
43 Disruption of VEGFR Signaling Leading to Developmental Defects BY-SA WPHA/WNT Endorsed
51 PPARα activation leading to impaired fertility in adult male rodents BY-SA Under Development
63 Cyclooxygenase inhibition leading to reproductive dysfunction BY-SA
64 Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility BY-SA
65 XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals BY-SA
66 Modulation of Adult Leydig Cell Function Subsequent Glucocorticoid Activation in the Fetal Testis BY-SA
67 Modulation of Adult Leydig Cell Function Subsequent to Estradiaol Activation in the Fetal Testis BY-SA
68 Modulation of Adult Leydig Cell Function Subsequent to Alterations in the Fetal Testis Protome BY-SA
73 Xenobiotic Inhibition of Dopamine-beta-Hydroxylase and subsequent reduced fecundity BY-SA
74 Modulation of Adult Leydig Cell Function Subsequent to Hypermethylation in the Fetal Testis BY-SA
94 Sodium channel inhibition leading to congenital malformations BY-SA
100 Cyclooxygenase inhibition leading to reproductive dysfunction via inhibition of female spawning behavior BY-SA
101 Cyclooxygenase inhibition leading to reproductive dysfunction via inhibition of pheromone release BY-SA
102 Cyclooxygenase inhibition leading to reproductive dysfunction via interference with meiotic prophase I /metaphase I transition BY-SA
103 Cyclooxygenase inhibition leading to reproductive dysfunction via interference with spindle assembly checkpoint BY-SA
106 Chemical binding to tubulin in oocytes leading to aneuploid offspring BY-SA Under Review
122 Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation BY-SA
123 Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription BY-SA
124 HMG-CoA reductase inhibition leading to decreased fertility BY-SA
126 Alpha-noradrenergic antagonism leads to reduced fecundity via delayed ovulation BY-SA
134 Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals BY-SA
146 Estrogen Receptor Activation and Female Precocious Puberty Open for adoption
152 Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity BY-SA Under Development
153 Aromatase Inhibition leading to Ovulation Inhibition and Decreased Fertility in Female Rats BY-SA
204 5-hydroxytryptamine transporter inhibition leading to increased reproductive success and population increase BY-SA
207 NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans BY-SA
208 Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) and Transforming growth factor (TGF)-beta pathways activation leading to reproductive failure BY-SA
210 Activation of c-Jun N-terminal kinase (JNK) and Forkhead box O (FOXO) and reduction of WNT pathways leading to reproductive failure: Integrated multi-OMICS approach for AOP building BY-SA
212 Histone deacetylase inhibition leading to testicular atrophy BY-SA WPHA/WNT Endorsed
218 Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity BY-SA
219 Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior BY-SA
271 Inhibition of thyroid peroxidase leading to impaired fertility in fish BY-SA Under Development
288 Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals) BY-SA
289 Inhibition of 5α-reductase leading to decreased population growth rate via impaired fecundity in female fish BY-SA Under Development
300 Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals BY-SA Under Development
305 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring BY-SA Under Review
306 Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring BY-SA Under Review
307 Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring BY-SA Under Review
309 Luteinizing hormone receptor antagonism leading to reproductive dysfunction BY-SA
310 Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR BY-SA
345 Androgen receptor (AR) antagonism leading to decreased fertility in females BY-SA Under Development
346 Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation BY-SA WPHA/WNT Endorsed
398 Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia BY-SA Under Development
400 Inhibition of CYP26B1 activity in fetal testis leading to reduced fertility BY-SA
442 Binding to voltage gate sodium channels during development leads to cognitive impairment BY-SA WPHA/WNT Endorsed
444 Ionizing radiation leads to reduced reproduction in Eisenia fetida via reduced spermatogenesis and cocoon hatchability BY-SA
458 AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals Open for adoption
459 AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals Open for adoption
465 Alcohol dehydrogenase leading to reproductive dysfunction BY-SA
476 Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity BY-SA
477 Androgen receptor (AR) antagonism leading to hypospadias in male (mammalian) offspring BY-SA
485 Thyroid hormone antagonism leading to impaired oligodendrocyte maturation during development and subsequent decreased cognition BY-SA
492 Glutathione conjugation leading to reproductive dysfunction via oxidative stress BY-SA
520 Retinoic acid receptor agonism during neurodevelopment leading to impaired learning and memory Open for adoption
521 Essential element imbalance leads to reproductive failure via oxidative stress BY-SA
525 Reduced oligodendrocyte differentiation during neurodevelopment leading to impaired learning and memory Open for adoption
526 Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Impaired, Spermatogenesis BY-SA
527 Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Hypospadias, increased BY-SA
528 Decreased Insulin-like peptide 3 (INSL3) leads to Malformation, cryptorchidism - maldescended testis BY-SA
533 Retinoic acid receptor antagonism during neurodevelopment leading to impaired learning and memory Open for adoption
537 Estrogen receptor agonism leads to reduced fecundity via increased vitellogenin in the liver BY-SA
540 Oxidative Stress in the Fish Ovary Leads to Reproductive Impairment via Reduced Vitellogenin Production BY-SA
547 Androgen receptor agonism leading to long anogenital distance (AGD) in female offspring All rights reserved
549 Aromatase inhibition leads to reproductive toxicity (including growth and developmental toxicity) in adult female zebrafish BY-SA
566 Decreased, GnRH pulsatility/release leading to estradiol availability, increased via impaired ovulation BY-SA
570 Decreased testosterone synthesis leading to hypospadias in male (mammalian) offspring BY-SA
571 5α-reductase inhibition leading to hypospadias in male (mammalian) offspring BY-SA
581 Glucocorticoid receptor (GR) activation during development leads to cognitive function (COG) decrease All rights reserved
595 Emerging OPFRS reproductive outcome pathway BY-SA
609 Activation, estrogen receptor alpha leads to prolonged estrus cycle via decreased kisspeptin release BY-SA
616 organic UV filter and its Photoproducts reproductive toxicity pathways All rights reserved
620 The Adverse Outcome Pathway to Deposition of Energy Leading to Female Decreased Fertility All rights reserved
623 Activation, estrogen receptor alpha leads to persistent vaginal cornification via increased kisspeptin release BY-SA
639 Activation, estrogen receptor alpha leads to precocious puberty via increased kisspeptin release BY-SA
640 Activation, estrogen receptor alpha leads to decreased fertility via prolonged estrus cycle BY-SA
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