A mechanistic model for thiol redox dynamics in the organogenesis stage rat conceptus

Precise control of the glutathione/glutathione disulfide (GSH/GSSG) redox balance is vital for the developing embryo, but regulatory mechanisms are poorly understood. We developed a novel, mechanistic mass-balance model for GSH metabolism in the organogenesis stage (gestational day 10.0-11.13) rat conceptus predicting the dynamics of 8 unique metabolites in 3 conceptal compartments: the visceral yolk sac (VYS), the extra-embryonic fluid (EEF) and the embryo proper (EMB). Our results show that thiol concentrations in all compartments are well predicted by the model. Protein synthesis is predicted to be a major efflux pathway for all amino acid precursors of GSH synthesis and an essential model element. Our model provides quantitative insights in the transport fluxes and enzymatic fluxes needed to maintain thiol redox balances under normal physiological conditions. This is crucial to further elucidate the mechanisms through which chemical exposure can perturb redox homeostasis, causing oxidative stress, and potentially birth defects.