Review: In vitro Cell Platform for Understanding Developmental Toxicity

Abstract

Developmental toxicity and its affiliation to long-term health, particularly neurodegenerative disease (ND) has attracted significant attentions in recent years. There is, however, a significant gap in current models to track longitudinal changes arising from developmental toxicity. The advent of induced pluripotent stem cell (iPSC) derived neuronal culture has allowed for more complex and functionally active in vitro neuronal models. Coupled with recent progress in the detection of ND biomarkers, we are equipped with promising new tools to understand neurotoxicity arising from developmental exposure. This review provides a brief overview of current progress in neuronal culture derived from iPSC and in ND markers.

Motor dysfunction in Drosophila melanogaster as a biomarker for developmental neurotoxicity

“…Therefore, there is a need for adequate alternatives to conventional animal testing for neurotoxicity and DNT ( Bal-Price et al., 2012 ). Hence, efforts are being directed toward the development of alternative models, utilizing either mammalian cells in culture or non-mammalian model systems, with the inclusion of new testing strategies to facilitate transition to more mechanistically based approaches ( Xie et al., 2020 ). Such approaches can unveil mechanistic cues that can assist in optimizing sensitive and practical assay endpoints for pathway-specific screening and the determination of predictive key events, which can be used as biomarkers for specific neurotoxic outcomes ( Bal-Price and Meek, 2017 ).…”

Co-Culture Models: Key Players in In Vitro Neurotoxicity, Neurodegeneration and BBB Modeling Studies

“…Humans are exposed daily to several potentially toxic chemicals present in the environment that, given their lipophilic nature, can easily cross the BBB and induce neurotoxicity. Among these environmental chemicals are the heavy metals, such mercury, and organic chemicals, such as pesticides and industrial surfactants [ 133 , 134 ]. In fact, several studies linked this exposure to neurodevelopment disorders and neurodegenerative diseases [ 133 , 134 ].…”

“…Among these environmental chemicals are the heavy metals, such mercury, and organic chemicals, such as pesticides and industrial surfactants [ 133 , 134 ]. In fact, several studies linked this exposure to neurodevelopment disorders and neurodegenerative diseases [ 133 , 134 ]. Given the inherent limitations of primary and immortalized endothelial cells, and that even with co-culture they still fail to approach the TEER values observed in vivo, an easy solution would be to perform more detailed/mechanistic studies at the target level, directly in the neuronal cells.…”

“…Given the inherent limitations of primary and immortalized endothelial cells, and that even with co-culture they still fail to approach the TEER values observed in vivo, an easy solution would be to perform more detailed/mechanistic studies at the target level, directly in the neuronal cells. The truth is that developments in the field of translational toxicology make it possible to seek complementary information, namely permeability of compounds at the BBB level to, for example, in silico assays [ 133 , 134 ]. Thus, eliminating the need to use endothelial cells as a barrier model, the focus becomes the neuronal response, which also benefits from co-culture with other cells.…”

Motor dysfunction in Drosophila melanogaster as a biomarker for developmental neurotoxicity

“…Therefore, there is a need for adequate alternatives to conventional animal testing for neurotoxicity and DNT (Bal-Price et al, 2012). Hence efforts are being directed toward the development of alternative models, utilizing either mammalian cells in culture or non-mammalian model systems, with the inclusion of new testing strategies to facilitate transition to more mechanistically based approaches (Xie et al, 2020). Such approaches can unveil mechanistic cues that can assist in optimizing sensitive endpoints for pathway-specific screening and the determination of predictive key events, which motor system of internal and external manipulations such as increased body load or lack of a particular neurotransmitter, amongst others (Enriquez et al, 2015;Howard et al, 2019;Mendes et al, 2014;Schretter et al, 2018).…”