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1.
Toxicology ; 500: 153684, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38029956

RESUMEN

in vitro screening platforms to assess teratogenic potential of compounds are emerging rapidly. ReproTracker is a human induced pluripotent stem cells (hiPSCs)-based biomarker assay that is shown to identify the teratogenicity potential of new pharmaceuticals and chemicals reliably. In its current state, the assay is limited to identifying the potential teratogenic effects and does not immediately quantify a clinical dose relevant to the exposure of chemicals or drugs observable in mothers or fetuses. The goal of this study was to evaluate whether the ReproTracker assay can be extrapolated in vivo and quantitatively predict developmental toxicity exposure levels of two known human teratogens, thalidomide, and carbamazepine. Here, we utilized Physiologically Based Pharmacokinetic (PBPK) modeling to describe the pharmacokinetic behavior of these compounds and conducted an in vitro to in vivo extrapolation (IVIVE) approach to predict human equivalent effect doses (HEDs) that correspond with in vitro concentrations potentially associated with adverse outcomes in ReproTracker. The HEDs derived from the ReproTracker concentration predicted to cause developmental toxicity were close to the reported teratogenic human clinical doses and the HED derived from the rat or rabbit developmental toxicity study. The ReproTracker derived-HED revealed to be sensitive and protective of humans. Overall, this pilot study demonstrated the importance of integrating PBPK model in extrapolating and assessing developmental toxicity in vitro. The combination of these tools demonstrated that they could improve the safety assessment of drugs and chemicals without animal testing.


Asunto(s)
Células Madre Pluripotentes Inducidas , Modelos Biológicos , Humanos , Ratas , Animales , Conejos , Proyectos Piloto , Teratógenos/toxicidad
2.
Birth Defects Res ; 114(19): 1210-1228, 2022 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-35289129

RESUMEN

BACKGROUND: Testing for developmental toxicity according to the current regulatory guidelines requires large numbers of animals, making these tests very resource intensive, time-consuming, and ethically debatable. Over the past decades, several alternative in vitro assays have been developed, but these often suffered from low predictability and the inability to provide a mechanistic understanding of developmental toxicity. METHODS: To identify embryotoxic compounds, we developed a human induced pluripotent stem cells (hiPSCs)-based biomarker assay. The assay is based on the differentiation of hiPSCs into functional cardiomyocytes and hepatocytes. Proper stem cell differentiation is investigated by morphological profiling and assessment of time-dependent expression patterns of cell-specific biomarkers. In this system, a decrease in the expression of the biomarker genes and morphology disruption of the differentiated cells following compound treatment indicated teratogenicity. RESULTS: The hiPSCs-based biomarker assay was validated with 21 well-established in vivo animal teratogenic and non-teratogenic compounds during cardiomyocyte and hepatocyte differentiation. The in vivo teratogenic compounds (e.g., thalidomide and valproic acid) markedly disrupted morphology, functionality, and the expression pattern of the biomarker genes in either one or both cell types. Non-teratogenic chemicals generally had no effect on the morphology of differentiated cells, nor on the expression of the biomarker genes. Compared to the in vivo classification, the assay achieved high accuracy (91%), sensitivity (91%), and specificity (90%). CONCLUSION: The assay, which we named ReproTracker®, is a state-of-the-art in vitro method that can identify the teratogenicity potential of new pharmaceuticals and chemicals and signify the outcome of in vivo test systems.


Asunto(s)
Células Madre Pluripotentes Inducidas , Teratogénesis , Animales , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Pruebas de Toxicidad/métodos , Teratógenos/farmacología , Diferenciación Celular , Biomarcadores/metabolismo
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