Non-human primate and rodent embryonic stem cells are differentially sensitive to embryotoxic compounds

Abstract

Many industrial chemicals and their respective by-products need to be comprehensively evaluated for toxicity using reliable and efficient assays. In terms of teratogenicity evaluations, the murine-based embryonic stem cell test (EST) offers a promising solution to screen for multiple tissue endpoints. However, use of a mouse model in the EST can yield only a limited understanding of human development, anatomy, and physiology. Non-human primate or human in vitro models have been suggested to be a pharmacologically and pathophysiologically desirable alternative to murine in vitro models. Here, we comparatively evaluated the sensitivity of embryonic stem cells (ESCs) of a non-human primate to skeletal teratogens with mouse ESCs hypothesizing that inclusion of non-human primate cells in in vitro tests would increase the reliability of safety predictions for humans. First, osteogenic capacity was compared between ESCs from the mouse and a New World monkey, the common marmoset. Then, cells were treated with compounds that have been previously reported to induce bone teratogenicity. Calcification and MTT assays evaluated effects on osteogenesis and cell viability, respectively. Our data indicated that marmoset ESCs responded differently than mouse ESCs in such embryotoxicity screens with no obvious dependency on chemical or compound classes and thus suggest that embryotoxicity screening results could be affected by species-driven response variation. In addition, ESCs derived from rhesus monkey, an Old World monkey, and phylogenetically closer to humans than the marmoset, were observed to respond differently to test compounds than marmoset ESCs. Together these results indicate that there are significant differences in the responses of non-human primate and mouse ESC to embryotoxic agents.

Keywords

• Osteogenesis
• Embryonic stem cell test
• Marmoset
• Rhesus
• Sensitivity
• Embryotoxicity