AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor–Responsive Genes in Target Tissues

IF 3.6 4区环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES

Environmental Toxicology and Chemistry Pub Date : 2024-08-29 DOI:10.1002/etc.5972

Monica K. Draskau, Anna K. Rosenmai, Nora Bouftas, Hanna K. L. Johansson, Eleftheria M. Panagiotou, Marie L. Holmer, Emilie Elmelund, Johanna Zilliacus, Anna Beronius, Pauliina Damdimopoulou, Majorie van Duursen, Terje Svingen

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Abstract

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen-sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine-disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP-wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross-species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;43:2329–2337. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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AOP 报告：雄激素信号减少导致靶组织中雄激素受体反应基因表达改变的上游网络。

不良后果途径（AOPs）可以在分子水平的化学活动与完整生物体内的效应结果之间提供可信的联系，从而帮助进行化学品风险评估。由于 AOP 可用于推断毒理学途径中上游和下游事件之间的因果关系，因此 AOP 框架还可促进更多替代方法和新方法的采用，为危害识别提供信息。然而，一个普遍存在的挑战是，完全开发并得到认可的 AOP 数量有限，这主要是由于 AOP 开发人员和审查人员需要做大量的工作。因此，有人提出了一种更加务实的 AOP 开发方法，即开发和审查独立于完整 AOP 的较小知识单元。在此背景下，我们开发了一个上游网络，该网络由与雄激素信号传导下降相关的关键事件（KEs）和关键事件关系组成，汇聚于一个节点KE，该节点KE可延伸至与雄激素敏感毒理途径相关的众多不良结果（AOs）。雄激素信号传导是一种被广泛研究的内分泌干扰途径。它与许多疾病结果有关，并可能受到许多不同的干扰内分泌的化学物质的影响。尽管如此，与雄激素信号干扰有关的途径在 AOP-wiki 中的代表性仍然不足，并且缺乏认可的 AOP。鉴于雄激素信号在脊椎动物类群和两性生命阶段的发育和功能中的关键作用，这一上游 AOP 网络是开发众多 AOP 的基础要素。通过将上游网络与包括不同物种在内的各种下游 AOs 相连接，它还可以促进跨物种推断，从而对化学品进行危害和风险评估。环境毒物化学 2024;00:1-9。© 2024 作者。环境毒理学与化学》由 Wiley Periodicals LLC 代表 SETAC 出版。

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来源期刊

Environmental Toxicology and Chemistry 环境科学-毒理学

CiteScore

7.40

自引率

9.80%

发文量

265

审稿时长

3.4 months

期刊介绍： The Society of Environmental Toxicology and Chemistry (SETAC) publishes two journals: Environmental Toxicology and Chemistry (ET&C) and Integrated Environmental Assessment and Management (IEAM). Environmental Toxicology and Chemistry is dedicated to furthering scientific knowledge and disseminating information on environmental toxicology and chemistry, including the application of these sciences to risk assessment.[...] Environmental Toxicology and Chemistry is interdisciplinary in scope and integrates the fields of environmental toxicology; environmental, analytical, and molecular chemistry; ecology; physiology; biochemistry; microbiology; genetics; genomics; environmental engineering; chemical, environmental, and biological modeling; epidemiology; and earth sciences. ET&C seeks to publish papers describing original experimental or theoretical work that significantly advances understanding in the area of environmental toxicology, environmental chemistry and hazard/risk assessment. Emphasis is given to papers that enhance capabilities for the prediction, measurement, and assessment of the fate and effects of chemicals in the environment, rather than simply providing additional data. The scientific impact of papers is judged in terms of the breadth and depth of the findings and the expected influence on existing or future scientific practice. Methodological papers must make clear not only how the work differs from existing practice, but the significance of these differences to the field. Site-based research or monitoring must have regional or global implications beyond the particular site, such as evaluating processes, mechanisms, or theory under a natural environmental setting.