Superfund Research Program
TCDD Impedes the Minimal Activation Threshold Required for Initiation of B Cell Differentiation: An Integrated Experimental and Computational Modeling Approach
Project Leader: Norbert E. Kaminski
Grant Number: P42ES004911
Funding Period: 2000-2021
Project-Specific Links
Datasets
Final Progress Reports
PublicationsFinal Progress Reports
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of a family of environmental contaminants termed, halogenated aromatic hydrocarbons (HAH), which are globally pervasive. The focus of the Michigan State University Superfund Research Center, and the Characterization of the Pathways Linking Ah Receptor Activation with Altered β Cell Differentiation Using an Integrated Experimental and Computational Modeling Approach project , on TCDD and dioxin-like compounds is of particular toxicological significant to the State of Michigan and specifically to the areas along the Tittabawassee River in Saginaw, Bay, and Midland counties where some of the highest concentrations in the world were identified. Parcels of contaminated land and sediments in the rivers and floodplains, including many residential areas in the City of Midland, were declared a Superfund site in 2007, raising significant concerns within the community of the long-term health consequences.
Suppression of the immune system and in particular of antibody production, a primary mechanism by which the body affords defense against infectious agents, is a hallmark of exposure to TCDD. Previous studies in laboratory animals by this and many others laboratories have shown that β cells, a type of white blood cell responsible for producing protective antibodies, is significantly impaired by TCDD treatment. The impairment of antibody production can lead to increased susceptibility to disease causing pathogens. The overall goal of this project study is to understand how TCDD and related environmental contaminants impair β cell function, specifically human β cells, and then to determine at what concentrations of TCDD exposure no effect on human β cell function is observed.
A major challenge to ultimately predicting safe levels of exposure to TCDD and dioxin-like compounds is that in the environments these agents typically exist as mixtures comprised of multiple members of agents from the same general family. Each family member has different potency based on its chemical structure. In order to better predict that potency and specifically the toxicity on antibody production of mixtures of dioxin-like compounds, in this project the researchers have partnered with investigators termed computational biologists. The role of computational biologists in this project is to take laboratory results obtained from studies investigating the effects of TCDD and dioxin-like compounds on human β cells and to then develop mathematical models that describe the biological effects.
An important question is how can mathematical models be applied to complex toxicologic questions? One can depict the biochemical reactions, which control β cell functions in a manner analogous to an electrical schematic comprised of a series of switches connected by wires. From laboratory studies, it is possible to identify specific biological switches, how they are connected and in which order. In addition, it is possible from laboratory studies to determine the threshold, or the amount of stimulus from an agent, that is required to "flip" these switches, which ultimately govern how the cell functions. Computational biologists working in collaboration with experimental toxicologists are able to translate information from laboratory experiments studying biological responses and describe them mathematically. Once the mathematical model has been developed, the computational biologist, with the aid of computers, can conduct simulations in order to determine if the model can recapitulate the biological responses observed, in this case by β cells in the laboratory. In addition, computational biologists using these models can also make predictions concerning biological responses that have not yet been determined in the laboratory. Experimental toxicologist can then conduct experiments in order to assess the validity of the model.
During the current funding period such studies were conducted in order to develop mathematical models that would describe as well as predict how TCDD and dioxin-like compounds alter the ability of β cells to produce antibodies. These studies showed that impairment of β cell function, as determined by suppression of antibody production by TCDD occurs in an all-or-none (binary) rather than graded manner (i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the antibody content in individual β cells). The mathematical model of the gene regulatory circuit underpinning β cell antibody production revealed that two previously identified pathways (inhibition of signaling protein AP-1 and activation of transcription factor Bach2), could account for the all-or-none mode of β cell suppression. The model further predicted that by activating a specific gene, termed Bach2, TCDD and dioxin-like compounds might delay β cells from producing certain types of antibodies, termed isotypes, which can be more or less protective against certain infectious agents. In conclusion, these studies allowed for the development of mathematical models that describe the manner and specific pathways inside β cells by which the environmental contaminants termed dioxin-like compounds suppress antibody production. The next phase of these studies will be to apply the existing mathematical models to predict the potency of mixtures of dioxin-like compounds on β cell function. Equally important, as these mathematical models become more refined, it may be possible to decrease the cost of assessing the relative risk of these chemicals by conducting much of the safety assessment mathematically rather than at the laboratory bench.