Dynamic changes in energy metabolism upon embryonic stem cell differentiation support developmental toxicant...

Area of Science:

• Developmental toxicology
• Stem cell biology
• Metabolomics

Background:

• Embryonic stem cells (ESCs) are vital for studying development and identifying developmental toxicants using the embryonic stem cell test (EST).
• Energy metabolism is critical for embryonic development, but its modulation in in vitro models like the EST remains underexplored.

Purpose of the Study:

• To characterize metabolic changes during early ESC differentiation using whole genome expression data.
• To define a gene set reflecting this energy metabolism profile.
• To validate the utility of this gene set in the EST for identifying specific developmental toxicants.

Main Methods:

• Transcriptomic analysis of ESCs undergoing early differentiation.
• Bioinformatic analysis to identify key metabolic pathways and define a relevant gene set.
• Application of the defined gene set within the EST framework.

Main Results:

• Early ESC differentiation activates glycolysis, lipid synthesis, and glutaminolysis, with truncated tricarboxylic acid (TCA) cycle activity.
• A defined gene set accurately reflects this specific energy metabolism profile.
• The gene set successfully identified known developmental toxicants (5-fluorouracil, methoxyacetic acid) that modulate cellular biosynthesis within the EST.

Conclusions:

• ESC differentiation involves a distinct energy metabolism reprogramming geared towards biosynthesis.
• The developed gene set provides a novel tool for the EST to identify toxicants impacting cellular biosynthesis.
• This research advances the understanding and applicability domain of the EST in developmental toxicology.