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: 2000-2020
Suppression of antibody responses is a hallmark of exposure to dioxin-like compounds. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of this family of environmental contaminants. Studies in laboratory animals by project researchers have shown that B lymphocytes, a type of white blood cell responsible for producing protective antibodies against pathogens, is significantly impaired by TCDD treatment. Mechanistic studies demonstrated a specific type of protein, termed a kinase, to be responsible for altered antibody secretion. These experiments led to the identification of a population of human B cells termed innate-like B cells that exhibit significant sensitivity to suppression by TCDD. The researchers also demonstrated that a protein called interferon gamma can reverse the effects of TCDD on B cells.
In addition, in collaboration with Center investigators, project researchers previously demonstrated that activated carbon (AC) may be a highly effective and inexpensive material for remediating environmental contamination of dioxins. Dioxins bind very tightly to AC blocking intestinal absorption and toxicity while not disrupting the microorganisms that populate the intestine, compared to administrated TCDD orally to mice. In most recent investigations, the researchers show that three commercially available ACs, representing a wide range of pore size distributions, were equally effective in eliminating the bioavailability of TCDD.
Last, collaborative work with investigators specializing in mathematical modeling of biological responses led to a new understanding of the mechanisms by which TCDD alters liver function and this approach will now be applied to B cells using new technologies termed single cell RNA sequencing.