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
Final Progress Reports
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 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 (Blevins 2021). 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 team also demonstrated that a protein called interferon gamma can reverse the effects of TCDD on B cells (Blevins 2020).
In addition, human cord blood-derived stem cells were used to understand the mechanisms by which TCDD alters the development of white blood cells, specifically B cells, from stem cells using a new technique termed single cell RNAseq which identified specific genes in individual cells that are adversely affected by TCDD (Khan 2021).
Last, in collaboration with their program investigators, the project team evaluated the effects of natural organic matter (NOM) on its ability to sequester TCDD (Yuan 2021). An aqueous suspension of TCDD mixed with NOM was administered to mice orally. These experiments demonstrated that TCDD poorly bound to the NOM and was readily taken up in the gastrointestinal tract with no protection when administered to animals (Yuan 2021). This work simulates exposure of humans, especially children who may be exposed to TCDD contaminated soils.