Developmental dioxin exposure reprograms hematopoietic stem cell differentiation capacity: Implications for immune system function and health outcomes across the lifespan

BACKGROUND: Incidence of immune disorders such as asthma, allergies, diabetes and other autoimmune diseases is increasing. It is estimated that over 25% of children in developed countries have an immune disorder. People worldwide are exposed through dietary intake to low levels of persistent environmental contaminants such as dioxin, but a link between these exposures and immunodeficiency has not been established. However, there exists a growing body of evidence supporting the hypothesis that fetal exposures are the basis for many adult diseases. For diseases of the immune system, potential targets of environmental exposures are hematopoietic stem cells (HSCs), which give rise to all blood cells. OBJECTIVE: This work tests the hypothesis that dioxin exposure in utero reprograms the capacity of HSCs to undergo lymphocyte differentiation. METHODS: Pregnant mice were exposed throughout gestation to 3µg/kg dioxin (10x lower levels than studied in adult mice). Fetal HSCs were harvested (day 14.5 of 21 day gestation), purified by flow cytometry, and grown in an in vitro co-culture system providing signals for immune (B- or T-) cell differentiation and development. After 12 days of co-culture, cells were collected, stained with antibodies to delineate immune cell development stage, and analyzed, using flow cytometry. The differentiation and fold expansion of B- and T-cells was determined. RESULTS: Preliminary data demonstrate that the capacity of mouse fetal HSCs to undergo B-cell differentiation is significantly reduced by in utero dioxin exposure (4.04-fold; p<0.005). T-cell differentiation is also attenuated (1.55-fold; p=0.02). The finding that fewer stem cells have the potential to undergo differentiation suggests potential epigenetic reprogramming. Future research will examine the mechanism(s) by which dioxin alters HSCs and the postnatal effects on phenotypic expression. These studies may help identify genetic biomarkers for screening and identifying susceptible populations and elucidate the pathway to immune disorders in humans across the lifespan.