Could a computational model reduce toxicity testing in animals?

Karen Watanabe, Ph.D., an assistant professor in the Division of Environmental & Biomolecular Systems at OHSU’s Institute of Environmental Health, uses computational models that mimic biological processes in hopes of reducing the number of laboratory animals used in toxicity testing.

Dr. Watanabe was recently awarded a grant from the Alternatives Research & Development Foundation that may help her do just that. The grant will fund a study to formulate a computational model of mammalian ovarian development to reduce animal testing of putative reproductive toxicants. She will use input data from in vitro studies that characterize chemical effects at the molecular and cellular levels to predict effects on ovarian development.

The first step in the project will be to compile published data to formulate a model with biologically based parameters that can utilize results from in vitro tests being developed under the paradigm of the U.S. National Academy of Sciences report Toxicity Testing for the 21st Century.  The landmark report released in 2007 envisions using computational systems biology models as one way to increase efficiency in toxicity testing and decrease animal usage.

The research team will formulate a conceptual model of the regulatory network involved in normal ovarian development. Then they will formulate a mathematical model that simulates the growth of the different cell populations (i.e., germ cells and somatic cells including granulosa cells, theca cells, and stromal cells) in the context of a developing ovary.

Outcomes of this research will include a computational model and a graphical representation of the biochemical regulatory network during ovarian development. The conceptual model will likely include a greater level of biological detail than the computational model that requires quantitative measurements of biological changes over time. Dr. Watanabe plans to implement a simplified version of the conceptual model and then revise it as additional data become available.

Dr. Watanabe has devoted her research career to developing computational models for a variety of biological systems including physiologically-based toxicokinetic models of benzene for rats, mice, and humans; bioaccumulation of polycyclic aromatic compounds in crayfish and aquatic food webs; and most recently the hypothalamic-pituitary-gonadal axis in male and female fathead minnows and oocyte growth dynamics in fathead minnows.

“We expect to have a computational model that will simulate molecular and cellular processes, and predict experimentally observed numbers of cells within a developing ovary from conception to the formation of primordial follicles,” Dr. Watanabe said.

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