Abstract
SummaryThe number of man-made chemicals has increased exponentially recently, and exposure to some of them can induce fetal malformations. Because complex and precisely programmed signaling pathways play important roles in developmental processes, their disruption by external chemicals often triggers developmental toxicity. However, highly accurate and high-throughput screening assays for potential developmental toxicants are currently lacking. In this study, we propose a reporter assay that utilizes human-induced pluripotent stem cells (iPSCs) to detect changes in fibroblast growth factor signaling, which is essential for limb morphogenesis. The dynamics of this signaling after exposure to a chemical were integrated to estimate the degree of signaling disruption, which afforded a good prediction of the capacity of chemicals listed in the ECVAM International Validation Study that induce limb malformations. This study presents an initial report of a human iPSC-based signaling disruption assay, which could be useful for the screening of potential developmental toxicants.
Highlights
7.9 million babies, which comprise 6% of the world’s birth population, are born annually with some form of congenital malformations (Christianson et al, 2006) that often require surgical treatment
We propose a reporter assay that utilizes human-induced pluripotent stem cells to detect changes in fibroblast growth factor signaling, which is essential for limb morphogenesis
The dynamics of this signaling after exposure to a chemical were integrated to estimate the degree of signaling disruption, which afforded a good prediction of the capacity of chemicals listed in the ECVAM International Validation Study that induce limb malformations
Summary
7.9 million babies, which comprise 6% of the world’s birth population, are born annually with some form of congenital malformations (Christianson et al, 2006) that often require surgical treatment. Malformations are caused by genetic factors and by the exposure to environmental factors, such as teratogenic chemicals, during fetal organogenesis. The tragedy with thalidomide in the 1950s and early 1960s highly influenced the official regulation for the use of potential developmental toxicants to which pregnant women may be exposed. Developmental toxicity studies have been conducted on pregnant animals by exposing them to chemicals such as industrial compounds, food additives, and agricultural pesticides. This approach detects the deleterious impact of such chemicals on the fetal development of multiple organs. Inexpensive, high-throughput, and highly predictive in vitro developmental toxicity assays are necessary
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