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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 TCDD-exposed 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.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Ahrenhoerster LS,Leuthner TC,Tate ER,Lakatos PA,Laiosa MD

doi

10.1016/j.taap.2014.12.017

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

99-108

issue

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(15)00003-4

journal_volume

283

pub_type

杂志文章

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