Human-Based New Approach Methodologies in Developmental Toxicity Testing: A Step Ahead from the State of the Art with a Feto-Placental Organ-on-Chip Platform

Abstract

Developmental toxicity testing urgently requires the implementation of human-relevant new approach methodologies (NAMs) that better recapitulate the peculiar nature of human physiology during pregnancy, especially the placenta and the maternal/fetal interface, which represent a key stage for human lifelong health. Fit-for-purpose NAMs for the placental-fetal interface are desirable to improve the biological knowledge of environmental exposure at the molecular level and to reduce the high cost, time and ethical impact of animal studies. This article reviews the state of the art on the available in vitro (placental, fetal and amniotic cell-based systems) and in silico NAMs of human relevance for developmental toxicity testing purposes; in addition, we considered available Adverse Outcome Pathways related to developmental toxicity. The OECD TG 414 for the identification and assessment of deleterious effects of prenatal exposure to chemicals on developing organisms will be discussed to delineate the regulatory context and to better debate what is missing and needed in the context of the Developmental Origins of Health and Disease hypothesis to significantly improve this sector. Starting from this analysis, the development of a novel human feto-placental organ-on-chip platform will be introduced as an innovative future alternative tool for developmental toxicity testing, considering possible implementation and validation strategies to overcome the limitation of the current animal studies and NAMs available in regulatory toxicology and in the biomedical field.

Keywords: OECD TG 414; adverse outcome pathways (AOPs); animal replacement; endocrine disruptors; new approach methodologies (NAMs).

Figure 1

Schematic representation of the AOP conceptual framework. The Molecular Initiating Event (MIE) is triggered by a stressor and determines a cascade of key events (KE) causally linked by key events relationships (KERs). For each step, different investigation approaches may be applied according to the increasing complexity of the biological level observed.

Figure 2

Requirements of a future feto–placental-OoC platform with the list of the cell type that can be implemented in the model. Fetal cells can be obtained from legal abortive material (9–12 weeks of gestation). A limited number of donors are required, also for amniotic and placenta cells. Immortalization of all these cell types will allow long-lasting availability of such cells. Possible associated chronic diseases which could be investigated through the model are indicated below each cell type.