Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis

Abstract

Over half of T-cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively active Notch1 transgene (Notch ICN-TG ). Following exposure of adult Notch ICN-TG mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3μg/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch ICN-TG offspring have a peripheral T-cell pool heavily biased toward the CD4 lineage, while TCDDexposed Notch ICN-TG offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression.

Repression of the Aryl Hydrocarbon Receptor Is Required to Maintain Mitotic Progression and Prevent Loss of Pluripotency of Embryonic Stem Cells

“…The increase of AHR expression may provide ES cells with the ability to respond to environmental insults and influence cell fate choices. Such as been the conclusion from studies in hematopoietic stem cells, where the untimely activation of AHR resulting from developmental exposure to TCDD impairs their long‐term self‐renewal capacity , and reduces their ability to commit to lymphocyte differentiation . Derailed stem cell regulation may lead to altered responses of T cells to viral infection and to unbalance the levels of Th17 and T reg cells , which may contribute to the etiology of multiple immunological disorders and autoimmune diseases .…”

Does the aryl hydrocarbon receptor regulate pluripotency?

“…Due to its functional duality between toxicity and normal physiology (Fig. 1) the AHR is uniquely positioned not only to convert signals from environmental toxicants into alterations of embryonic development, but to trigger a sustained state of cardiovascular insufficiency that increases the risk of adult disease [2, 8, 12-16]. Consonant with the postulates of the Barker Theory of the Developmental Origins of Health and Disease [17], developmental cardiac insufficiency may translate in the adult into congenital heart disease.…”

The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration

“…No further evidence of AHR-HEDGEHOG interaction in other tissues has been described to date. There is some evidence for AHR-NOTCH interactions [ 30 , 31 ] in the context of the development of the immune system; however, those observations indicate that these interactions affect potency and differentiation capacity rather than self-renewal.…”