title: Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis.
abstract: Gene-environment interactions determine the biological outcomes through mechanisms that are poorly understood. Mouse embryonic eyelid closure is a well defined model to study the genetic control of developmental programs. Using this model, we investigated how exposure to dioxin-like environmental pollutants modifies the genetic risk of developmental abnormalities. Our studies reveal that mitogen-activated protein 3 kinase 1 (MAP3K1) signaling is a focal point of gene-environment cross-talk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocked eyelid closure in genetic mutants in which MAP3K1 signaling was attenuated but did not disturb this developmental program in either wild type or mutant mice with attenuated epidermal growth factor receptor or WNT signaling. Exposure also markedly inhibited c-Jun phosphorylation in Map3k1(+/-) embryonic eyelid epithelium, suggesting that dioxin-induced AHR pathways can synergize with gene mutations to inhibit MAP3K1 signaling. Our studies uncover a novel mechanism through which the dioxin-AHR axis interacts with the MAP3K1 signaling pathways during fetal development and provide strong empirical evidence that specific gene alterations can increase the risk of developmental abnormalities driven by environmental pollutant exposure.
authors.affiliation: From the Departments of Environmental Health and.
authors.forename: Maureen
authors.initials: M
authors.lastname: Mongan
authors.affiliation: From the Departments of Environmental Health and.
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: From the Departments of Environmental Health and.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0056.
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.affiliation: From the Departments of Environmental Health and.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Puga
authors.affiliation: From the Departments of Environmental Health and Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0056 ying.xia@uc.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D004147:Dioxins / Q000633:toxicity*; D004622:Embryo, Mammalian; D004785:Environmental Pollutants / Q000633:toxicity*; D004848:Epithelium / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D005143:Eyelids / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D059647:Gene-Environment Interaction; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004147:Dioxins; D004785:Environmental Pollutants; D018336:Receptors, Aryl Hydrocarbon; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse
keywords: aryl hydrocarbon receptor (AhR) (AHR); c-Jun N-terminal kinase (JNK); dioxin; embryonic eyelid closure; gene-environment interaction; mitogen-activated protein 3 kinase 1 (MAP3K1); morphogenesis; signaling