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Systems Modeling in Developmental Toxicity
Citation:
KNUDSEN, T. B. AND R. DEWOSKIN. Systems Modeling in Developmental Toxicity. 1st Edition, Chapter 37, Daniel A. Casciano; Saura C. Sahu (ed.), Handbook of Systems Toxicology. John Wiley and Sons, LTD, , Uk, 2:599-617, (2011).
Impact/Purpose:
After suitable elaboration and verification, agent-based dynamic models may someday be used to simulate potential adverse effects following exposure to environmental chemicals where there is some information on perturbation to the model input functions. These models can be exercised to predict outcomes for conditions not experimentally practical because of cost, time, scale, or complexity. Newer technologies such as deep sequencing and cell-level transcriptomics, together with genetics and live cell imaging, bring together the potential to collect cell-level information in a dynamic, integrated system. As most teratology data are derived from perturbation of organogenesis, these newer technologies can provide detailed information at all stages of embryogenesis to provide a more complete system-level perspective such that various computational models would be more relevant with regards to human risk assessment. Because morphogenesis is more than a cumulative sum of individual cell behaviors, virtual tissue models that enable interactions of autonomous cells and preserve elements of system-level control can utilize extensive knowledge about the system and rapidly sweep potential developmental trajectories following chemical or genetic perturbation, thus providing deeper insight into mechanisms of toxicity than is possible solely by analyzing the cell-based data.
Description:
An individual starts off as a single cell, the progeny of which form complex structures that are themselves integrated into progressively larger systems. Developmental biology is concerned with how this cellular complexity and patterning arises through orchestration of cell divisions, cell migrations, cell interactions, cell death, gene regulation, and differentiation. Any agent interfering with these cellular processes can potentially invoke adverse effects on pregnancy outcome leading to miscarriage, low birth weight, structural malformations, and functional deficits. Windows of vulnerability open and close that render the embryo more or less susceptible to drug and chemical exposure at different times and locations. Developmental toxicology is concerned with understanding these underlying genetic and environmental influences and assessing the health risks from prenatal exposure to drugs and chemicals.
