Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity

Abstract

Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes. As such, AOPs are anticipated to facilitate the compilation of information to increase mechanistic understanding of pathophysiological pathways that are responsible for human disease.In this review, the sequence of key events resulting in adverse outcome (AO) defined as parkinsonian motor impairment and learning and memory deficit in children, triggered by exposure to environmental chemicals has been briefly described using the AOP framework. These AOPs follow convention adopted in an Organization for Economic Cooperation and Development (OECD) AOP development program, publically available, to permit tailored application of AOPs for a range of different purposes.Due to the complexity of disease pathways, including neurodegenerative disorders, a specific symptom of the disease (e.g. parkinsonian motor deficit) is considered as the AO in a developed AOP. Though the description is necessarily limited by the extent of current knowledge, additional characterization of involved pathways through description of related AOPs interlinked into networks for the same disease has potential to contribute to more holistic and mechanistic understanding of the pathophysiological pathways involved, possibly leading to the mechanism-based reclassification of diseases, thus facilitating more personalized treatment.

Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept

“…Furthermore, a recent consensus among various stakeholders (regulatory bodies, academia and industry) has been reached, arguing that a new testing framework based on alternative approaches is urgently needed to improve and speed up testing of chemicals for their DNT potential [34,77]. In this context, the obtained data suggest that the applied in vitro approach could be included in Integrated Approaches to Testing and Assessment (IATA) for different regulatory purposes, as recently suggested [16]. The battery of in vitro assays applied in this study (i.e., synaptogenesis, neurite outgrowth and BDNF levels) and the use of human neuronal in vitro models (avoiding the need to extrapolate between different species) would be suitable for an initial screening to identify chemicals with potential to trigger DNT effects, particularly those associated with learning and memory impairment in children.…”

“…To date, seven DNT AOPs have been developed [9][10][11][12][13][14][15] or are still under finalisation [14,16] in which cognitive damage, including learning and memory impairment in children has been identified as an AO. These AOPs are triggered by different molecular initiating events (MIEs) and various early key events (KEs), but three KEs before the AO are common KEs (CKEs) for most of them: (i) altered brain derived neurotrophic factor (BDNF) levels; (ii) altered synaptogenesis, and (iii) altered neuronal network function, as summarised in Fig.…”

Advancing human health risk assessment

“…Therefore, in this study, it was proposed to use a mixed culture of neuronal and glial cells derived from human induced pluripotent stem cells as this in vitro model makes it possible to evaluate a chemical impact on key neurodevelopmental processes (including cell proliferation, migration and morphological/functional neuronal and glial differentiation) mimicking critical stages of human brain development. Moreover, the applied in vitro assays were anchored to the selected neurodevelopmental processes that overlapped with common key events identified in AOPs relevant to impairment of learning and memory in children; this is the most frequent adverse outcome identified in the existing DNT AOPs (Bal‐Price and Meek, ). The effects of the selected compounds (administered as a single chemical or in mixtures) were assessed on human neural precursor cells undergoing differentiation to determine synergistic, antagonistic or additive effects on brain‐derived neurotrophic factor (BDNF) level, neurite outgrowth and synaptogenesis after short‐ (72 h) or long‐term exposure (14 days in vitro ).…”

Effects of atrazine on fish, amphibians, and reptiles: update of the analysis based on quantitative weight of evidence

“…A framework for the analysis of -omics data was developed by Bridges et al (2017) as was another framework for QWoE of reproductive and developmental toxicants Bridges 2016a, 2016b) and increasing the confidence in use of mode-of-action data to extrapolate risks to humans (Becker et al 2017;Dekant et al 2017). Others have suggested WoE can be used to assess information on adverse outcome pathways (Becker et al 2015;Bal-Price and Meek 2017;Brockmeier et al 2017;Browne et al 2017;Armstrong et al 2018) and weighted scores were used to characterize effects of atrazine in aquatic cosms (Giddings et al 2018). Our QWoE framework was used to categorize responses into levels of biological organization.…”