Proposal Abstract Many compounds, including medications, can cause birth defects or fetal loss when exposed to pregnant women. Although the concept of such compounds, i.e., teratogens, is well acknowledged, it is still challenging to identify which drugs are teratogenic. As new drugs are introduced to the market every year, it is crucial to conduct speedy and thorough investigations to assess their potential teratogenicity. Identification of teratogens requires multiple investigative approaches, such as human epidemiology, tests on pregnant animals, and in vitro assays using embryonic stem cells. In vitro assays are generally fast, economical, and expandable for high-throughput screening, and also are amenable for molecular analyses to provide mechanistic insight into teratogen actions. Currently, most in vitro assays with stem cells are designed to test impact of drugs on differentiation into specific cell types. However, many common birth defects, such as neural tube defects and heart septal defects, are misregulation of ?morphogenesis?, i.e., coordinated cell migration and rearrangement to construct 3-dimensional tissue architectures. My goal is to create new in vitro models that recapitulate morphogenesis of early embryos using mouse and human stem cells, which can be used to detect and analyze a wide range of teratogens.
In Specific Aim 1, we will employ the morphogenesis model to investigate teratogenic actions of a common antidepressant, fluoxetine, focusing on its inhibitory action against the key developmental signal that controls embryo patterning.
In Specific Aim 2, we will integrate metabolic conversions into the in vitro morphogenesis system to expand the capability of the model to detect compounds that become teratogenic only after metabolic modifications by the mother.
In Specific Aim 3, we will validate the accuracy of human cell-based morphogenesis model to distinguish between teratogenic and non-teratogenic compound exposures. These studies should provide solid foundation for developing new advanced tools for future teratogen research, which should help reduce tragic incidences of birth defects and fetal loss that are triggered by medicines that women of reproductive age are exposed to.
Proposal Narrative Environmental factors, such as medications, can hamper embryo development before implantation. To predict which factors may impair embryos, understanding of the molecular mechanisms behind embryo development is essential. The proposed research is to investigate the role of mevalonate pathway, the main target of common cholesterol-lowering drugs, in regulation of cell differentiation in early embryos.
| Kim, Iris Q; Marikawa, Yusuke (2018) Embryoid body test with morphological and molecular endpoints implicates potential developmental toxicity of trans-resveratrol. Toxicol Appl Pharmacol 355:211-225 |
| Warkus, Erica L L; Marikawa, Yusuke (2018) Fluoxetine Inhibits Canonical Wnt Signaling to Impair Embryoid Body Morphogenesis: Potential Teratogenic Mechanisms of a Commonly Used Antidepressant. Toxicol Sci 165:372-388 |
