Developmental biology meets toxicology: contributing reproductive mechanisms to build adverse outcome pathways

Abstract

An adverse outcome pathway (AOP) is a simplified description of the sequence of mechanistic events that lead to a particular toxicological effect, from initial trigger to adverse outcome. Although designed to inform regulatory risk assessors, the AOP framework also provides a platform for innovative collaborations between experts from relevant research fields and the regulatory community. The underpinning for any AOP is basic knowledge about molecular and developmental processes; such knowledge can only be attained by solid bioscientific research. Starting with this fundamental knowledge, the objective is to devise novel testing strategies that focus on key events in a causative pathway. It is anticipated that such a knowledge-based approach will ultimately alleviate many of the burdens associated with classical chemical testing strategies that typically involve large-scale animal toxicity regimens. This hails from the notion that a solid understanding of the underlying mechanisms will allow the development and use of alternative test methods, including both in vitro and in silico approaches. This review is specifically targeted at professionals working in bioscientific fields, such as developmental and reproductive biology, and aims to (i) inform on the existence of the AOP framework and (ii) encourage new cross-disciplinary collaborations. It is hoped that fundamental biological knowledge can thus be better exploited for applied purposes: firstly, an improved understanding of how our perpetual exposure to environmental chemicals is causing human reproductive disease and, secondly, new approaches to screen for harmful chemicals more efficiently. This is not an instructional manual on how to create AOPs; rather, we discuss how to harness fundamental knowledge from the biosciences to assist regulatory toxicologists in their efforts to protect humans against chemicals that harm human reproductive development and function.

Hedgehog signal disruption, gonadal dysgenesis and reproductive disorders: Is there a link to endocrine disrupting chemicals?

“…To do so, we need more cross-disciplinary interactions between experts from basic biology, toxicology and chemical risk assessors. And, as recently advocated ( Draskau et al, 2020 ), the AOP framework is a very good platform to facilitate such endeavors.…”

A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation

“…Typically, they do so at the molecular level (termed molecular initiating event; MIE) to a consequent adverse effect at a level of the biological organization considered relevant to risk assessment, regulatory decision-making, or management of environmental or human health (termed the adverse outcome [AO]; OECD, 2018 ). AOPs do not aim to faithfully depict the complex molecular and cellular events taking place in the living organisms in their entirety ( Draskau et al , 2020 ). Rather, AOPs are stripped-down versions of toxicity pathways focusing on a number of essential events that serve as milestones or landmarks along the progression toward an AO ( Ankley et al , 2010 ; Villeneuve et al , 2014a , b ).…”

A Putative Adverse Outcome Pathway Network for Disrupted Female Pubertal Onset to Improve Testing and Regulation of Endocrine Disrupting Chemicals

“…Although AOPs are similar to classical molecular pathways describing normal development or disease etiologies [35], there are clear distinctions. Firstly, an AOP should be of relevance to chemical risk assessment or regulatory decision-making.…”