Exposome and Exposure Modeling

Toxicodynamics - embryo glutathione

About this project

Precise control of the cellular redox balance is vital for the developing embryo. The cellular redox balance determines cell fate decisions (e.g. proliferation, differentiation and apoptosis) that are critical to ensure normal embryonic development. The redox balance can, however, be perturbed through exposure to toxicants or nutrient deficits resulting in oxidative stress (a shift from a normal reducing to overly oxidizing intracellular environment). An oxidizing environment during development can cause birth defects and has also been associated with an increased risk of postnatal chronic diseases including neurodegeneration, hypertension, cancer and type II diabetes. Despite its importance, it is presently not well understood how the redox state is maintained, regulated and modified over the course of mammalian embryonic development, and consequently, mechanisms through which endogenous or exogenous sources of oxidative stress disturb the redox balance, are poorly known.

We develop mathematical systems-biology based models to explain and predict how exposure to toxicants, such as MEHP, and nutrient deficits perturb redox homeostasis and/or associated signaling pathways. We use the organogenesis-stage rodent embryo as a model organism and work closely together with Prof. Craig Harris, an expert in rodent whole-embryo culture techniques and developmental toxicology. Ultimately, we hope to find answers to fundamental questions such as: Which chemicals can perturb embryonic redox homeostasis? What is the role of antioxidant defense mechanisms? Are there differences in sensitivity during embryonic development? And how do disturbances in redox homeostasis cause anatomical and functional birth defects?

Sponsor

Jolliet's lab

People

Karin Veltman

Olivier Jolliet (ojolliet@umichl.edu)

Craig Harris

Keywords

Pharmacodynamics, developmental toxicology, cysteine and glutathione balance, embryo

Project summary

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) (Fig.1). Our results show that thiol concentrations in all compartments are well predicted by the model (Fig.2). 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 (see Table 1 as example of the experimentally determined or calibrated parameters). This is crucial to further elucidate the mechanisms through which chemical exposure can perturb redox homeostasis, causing oxidative stress, and potentially birth defects.

Figure 1. Schematic overview of GSH metabolism in the organogenesis stage rat embryo. (Veltman et al., 2018)

Figure 2. Model predictions vs. empirical values (1:1 plot) for a) calibration data and b) literature-collected data.

Table 1. Parameters, literature reported values and calibrated values (with initial values in parentheses) for γ-glutamyl-cysteine formation and GSH formation in the VYS membrane (VYS) and the embryo proper (EMB) and transport of GSH and GSSG from the VYS and the EMB.

Publications

Veltman K, Harris C, Ahmad Y, Jolliet O, 2018. A mechanistic model for thiol redox dynamics in the organogenesis stage rat conceptus. Reproductive Toxicology, 82, 38-49.
Veltman K, Ahmad Y, Harris C, Jolliet O, 2017. Characterizing thiol redox dynamics in the organogenesis stage rat embryo. Free Radic Biol Med. 113 97-108.

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