Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development

Palermo, Christine; Foreman, Jennifer E.; Wikoff, Daniele; Lea, Isabel

doi:10.1016/j.crtox.2021.07.002

Cited by 7 publications

(4 citation statements)

References 124 publications

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“…Other AOPNs describing perturbations to different endocrine pathways have recently been described, albeit for different purposes and with different scopes. Several studies describe the development of AOPNs containing novel pathways as an alternative to postulating single AOPs, for example, related to disrupted female pubertal onset ( Franssen et al, 2022 ), male reproductive tract abnormalities ( Palermo et al, 2021 ), and for effects on male and female reproductive function in fish ( Ankley et al, 2023 ; Morshead et al, 2023 ). Others describe AOPNs for specific types of endocrine mediated toxicities and stressors, such as exploring male reproductive toxicity of silver nanoparticles ( Kose et al, 2023 ) and inorganic arsenic ( Chai et al, 2021 ), or the impact of phthalates on female reproduction ( Pogrmic-Majkic et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Any AOPN must therefore be assumed to be missing information necessary to, for example, reliably identify all relevant core KE(R)s. Indeed, we acknowledge that there are several putative or complete AOPs relevant for EAS-mediated reproductive toxicity published in the open literature but not necessarily entered into the wiki. For example, there are several AOPs describing effects on spermatogenesis and the development of the male reproductive tract, as well as nipple retention in rodents, or prostate and testis tumours caused by androgen receptor (AR) antagonism, estrogen receptor (ER) agonism or reduced testosterone levels via different mechanisms such as inhibition of aromatase, oxidative stress, AhR signalling, and retinoic acid signalling ( Christiansen et al, 2020 ; Draskau et al, 2020 ; Gray et al, 2020 ; Johnson et al, 2020 ; Kortenkamp, 2020 ; Yokel, 2020 ; Palermo et al, 2021 ; Silva da et al, 2021 ; Myden et al, 2022 ; Pedersen et al, 2022 ; Kose et al, 2023 ). A partial AOP for decreased gonadotropin-releasing hormone (GnRH) expression in hypothalamus leading to reduced testosterone production has been postulated ( Lu et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

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Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity

Zilliacus,

Draskau,

Johansson

et al. 2024

Front. Toxicol.

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Introduction: Adverse Outcome Pathways (AOPs) can support both testing and assessment of endocrine disruptors (EDs). There is, however, a need for further development of the AOP framework to improve its applicability in a regulatory context. Here we have inventoried the AOP-wiki to identify all existing AOPs related to mammalian reproductive toxicity arising from disruption to the estrogen, androgen, and steroidogenesis modalities. Core key events (KEs) shared between relevant AOPs were also identified to aid in further AOP network (AOPN) development.Methods: A systematic approach using two different methods was applied to screen and search the entire AOP-wiki library. An AOPN was visualized using Cytoscape. Manual refinement was performed to remove AOPS devoid of any KEs and/or KERs.Results: Fifty-eight AOPs relevant for mammalian reproductive toxicity were originally identified, with 42 AOPs included in the final AOPN. Several of the KEs and KE relationships (KERs) described similar events and were thus merged to optimize AOPN construction. Sixteen sub-networks related to effects on hormone levels or hormone activity, cancer outcomes, male and female reproductive systems, and overall effects on fertility and reproduction were identified within the AOPN. Twenty-six KEs and 11 KERs were identified as core blocks of knowledge in the AOPN, of which 19 core KEs are already included as parameters in current OECD and US EPA test guidelines.Discussion: The AOPN highlights knowledge gaps that can be targeted for further development of a more complete AOPN that can support the identification and assessment of EDs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity

Zilliacus,

Draskau,

Johansson

et al. 2024

Front. Toxicol.

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“…It used a decellularized intestinal submucosa, seeded with urothelial cells (260). Specific genes were discovered and involved in hypospadias formation in rats and mice (261)(262)(263)(264). Prenatal atrazine and vinclozolin exposure can affect penile and testicular development (265).…”

Section: Animal Modelsmentioning

confidence: 99%

Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review)

Gozar¹,

Bara²,

Dicu³

et al. 2023

Exp Ther Med

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Hundreds of papers are written about hypospadias every year referring to all aspects of the pathology, being one of the most common congenital malformations. The present study conducted a scoping review of articles published in 2021 to present the main issues and summarize current perspectives and achievements in the field. It searched for the keyword 'hypospadias' in the three most popular databases (PubMed, Scopus and Web of Science). After the analysis of the publications, they were categorized into different domains.

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“…This, alongside the lack of commensurate professional recognition of the scholarly effort invested in rigorous AOP development, is a major hurdle that prevents many potential AOP developers from either embarking on the task all together, or saps motivation once it becomes clear how much work is required. These points are also reflected in the discrepancy between “purely conceptual” or “putative” AOPs that have been published in the open literature, eg ( Barenys et al , 2020 ; Franssen et al , 2021 ; Johansson et al , 2020 ; Martinovic-Weigelt et al , 2017 ; Palermo et al , 2021 ; Vinken, 2020 ; Weiss et al , 2021 ; Yang et al , 2019 ), versus those that exist and are under active development in the AOP-wiki .…”

mentioning

confidence: 99%

A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation

Svingen

Villeneuve

Knapen

et al. 2021

Toxicological Sciences

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The adverse outcome pathway (AOP) framework provides a practical means for organizing scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. It has reached wide acceptance as a tool to aid chemical safety assessment and regulatory toxicology by supporting a systematic way of predicting adverse health outcomes based on accumulated mechanistic knowledge. A major challenge for broader application of the AOP concept in regulatory toxicology, however, has been developing robust AOPs to a level where they are peer-reviewed and accepted. This is because the amount of work required to substantiate the modular units of a complete AOP is considerable, to the point where it can take years from start to finish. To help alleviate this bottleneck, we propose a more pragmatic approach to AOP development whereby the focus becomes on smaller blocks. First, we argue that the key event relationship (KER) should be formally recognized as the core building block of knowledge assembly within the AOP-KB, albeit framing them within full AOPs to ensure regulatory utility. Second, we argue that KERs should be developed using systematic review approaches, but only in cases where the underlying concept does not build on what is considered canonical knowledge. In cases where knowledge is considered canonical, rigorous systematic review approaches should not be required. It is our hope that these approaches will contribute to increasing the pace at which the AOP-KB is populated with AOPs with utility for chemical safety assessors and regulators.

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Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development

Abstract: Graphical abstract

Cited by 7 publications

References 124 publications

Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity

Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity

Current perspectives in hypospadias research: A scoping review of articles published in 2021 (Review)

A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation

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