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Veronika Mantziou, Peter Baillie-Benson, Manuela Jaklin, Stefan Kustermann, Alfonso Martínez Arias, Naomi Moris
Pharmaceuticals intended for use in patients of childbearing potential need to be tested for teratogenicity before marketing. Several pharmaceutical companies use animal-free in vitro models which allow a more rapid selection of lead compounds and contribute to 3Rs principles ('replace, reduce and refine') by streamlining the selection of promising compounds submitted to further regulatory studies in animals. Currently available in vitro models typically rely on adherent monolayer cultures or disorganized 3D structures, both of which lack the spatiotemporal and morphological context of the developing embryo. A newly developed 3D 'gastruloid' model has the potential to achieve a more reliable prediction of teratogenicity by providing a robust recapitulation of gastrulation-like events alongside morphological coordination at relatively high-throughput. In this first proof-of-concept study, we used both mouse and human gastruloids to examine a panel of seven reference compounds, with associated in vivo data and known teratogenic risk, to quantitatively assess in vitro teratogenicity. We observed several gross morphological effects, including significantly reduced elongation or decreased size of the gastruloids, upon exposure to several of the reference compounds. We also observed aberrant gene expression using fluorescent reporters, including SOX2, BRA, and SOX17, suggestive of multi-lineage differentiation defects and disrupted axial patterning. Finally, we saw that gastruloids recapitulated some of the known in vivo species-specific susceptibilities between their mouse and human counterparts. We therefore suggest that gastruloids represent a powerful tool for teratogenicity assessment by enabling relevant physiological recapitulation of early embryonic development, demonstrating their use as a novel in vitro teratogenic model system.
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Mantziou, V., Baillie-Benson, P., Jaklin, M., Kustermann, S., Arias, A. M., & Moris, N. (2021). In vitro teratogenicity testing using a 3D, embryo-like gastruloid system. Reproductive Toxicology, 105, 72–90. https://doi.org/10.1016/j.reprotox.2021.08.003
Mantziou, Veronika, et al. "In vitro teratogenicity testing using a 3D, embryo-like gastruloid system." Reproductive Toxicology, vol. 105, 2021, pp. 72–90, https://doi.org/10.1016/j.reprotox.2021.08.003.
Mantziou, Veronika, Peter Baillie-Benson, Manuela Jaklin, Stefan Kustermann, Alfonso Martínez Arias, and Naomi Moris. "In vitro teratogenicity testing using a 3D, embryo-like gastruloid system." Reproductive Toxicology 105 (2021): 72–90. https://doi.org/10.1016/j.reprotox.2021.08.003.
Mantziou V., Baillie-Benson P., Jaklin M. [и др.] In vitro teratogenicity testing using a 3D, embryo-like gastruloid system // Reproductive Toxicology. — 2021. — Vol. 105. — P. 72–90. — URL: https://doi.org/10.1016/j.reprotox.2021.08.003
@article{mantziou2021vitro,
title = {{In vitro teratogenicity testing using a 3D, embryo-like gastruloid system}},
author = {Veronika Mantziou and Peter Baillie-Benson and Manuela Jaklin and Stefan Kustermann and Alfonso Martínez Arias and Naomi Moris},
journal = {Reproductive Toxicology},
year = {2021},
volume = {105},
pages = {72--90},
doi = {10.1016/j.reprotox.2021.08.003},
url = {https://doi.org/10.1016/j.reprotox.2021.08.003}
}TY - JOUR AU - Mantziou, Veronika AU - Baillie-Benson, Peter AU - Jaklin, Manuela AU - Kustermann, Stefan AU - Arias, Alfonso Martínez AU - Moris, Naomi TI - In vitro teratogenicity testing using a 3D, embryo-like gastruloid system JO - Reproductive Toxicology VL - 105 SP - 72 EP - 90 PY - 2021 DA - 2021/08/20 DO - 10.1016/j.reprotox.2021.08.003 UR - https://doi.org/10.1016/j.reprotox.2021.08.003 ER -
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