title: 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.
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Ahrenhoerster
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.
authors.forename: Tess C
authors.initials: TC
authors.lastname: Leuthner
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.
authors.forename: Everett R
authors.initials: ER
authors.lastname: Tate
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lakatos
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address: laiosa@uwm.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Laiosa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013945:Thymoma / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology
chemical_list: C497762:Notch1 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; D051881:Receptor, Notch1
keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; Aryl hydrocarbon receptor; Developmental immunotoxicology; Gene–environment interaction; Leukemogenesis; Notch1