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.

Creating mini-pregnancy models in vitro with clinical perspectives

“…Research on drug transfer to a foetus from mother has been limited to indirect methods such as measuring the concentration of medication from umbilical cord blood at the timing of delivery or animal experiments. 62 Because the effective administration of most drugs on the development of a foetus during pregnancy remains unanswered, organ chips or other devices remodelling maternal–foetal interface to evaluate drug transfer are valuable fields of research.…”

Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

“…Although essential, in vivo toxicity testing comes with challenges in predicting human responses and several ethical issues related to the suffering of animals, besides being low-throughput, costly, and labor intensive. The current golden standard for developmental toxicity testing/embryotoxicity testing accepted by regulatory bodies is described in the OECD test guideline 414 (Luconi et al 2022 ; Piersma et al 2022 ). This guideline describes how rodents, predominantly rats and rabbits are exposed to chemicals throughout a full gestation period whereafter the effects on embryonic/fetal development are assessed upon killing of the animal one day before delivery (OECD 2018 ).…”

A perspective on molecular and cellular biology-based developmental toxicology biomarkers

“…Prior to that, different substances were being examined on adults, but infrequent testing was carried out on pregnant animals, and it was widely believed that the placental barrier protected the foetus from outside agents. Additionally, there has been significant progress made to identify probable developmental toxins in the environment and control human exposure to them since the beginning of the sixties, when prenatal sensitivity was first recognized (Estevan et al, 2017;Luconi et al, 2022). In addition to birth problems, growth retardation, mortality (including the loss of embryos and foetuses), and functional impairments in the newborn are increasingly recognized as detrimental developmental impacts (Draskau et al, 2020).…”

“…In addition to birth problems, growth retardation, mortality (including the loss of embryos and foetuses), and functional impairments in the newborn are increasingly recognized as detrimental developmental impacts (Draskau et al, 2020). In laboratory animals, over 1,200 distinct substances have been found to have detrimental developmental consequences; however, the implications of exposure to many of these substances in humans are not well known (Giavini and Menegola, 2012;Luconi et al, 2022).…”

“…Risk analysts typically depend on two types of data to make risk predictions: estimations of human toxication extent to a specific substance and assessments of the substance's human toxicity according to developmental/embryonic outcomes of progeny from trial mothers-to-be subjected to that compound (Hougaard, 2021). Sometimes, data becomes accessible from other avenues, such as (1) relationships between structure and activity connecting the substance's toxicity with its other family members, (2) the outcomes of the chemical's in vitro experiments, and (3) human epidemiology findings regarding the compound's impact (Committee on Developmental Toxicology, 2000;Luconi et al, 2022).…”