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.
Highlights
Adverse health effects may result from the synergy between environmental exposures and genetic makeup
We explored the genetic influences of dioxin exposure in the embryonic eyelid closure model and identified a novel gene-environment interaction mechanism in TCDD teratogenicity
TCDD Exposure Synergies with Mutants of Map3k1, but Not Wnt or Egfr, in Perturbing Embryonic Eyelid Closure—The eyelid starts to close between GD15.5 and GD16.5
Summary
Adverse health effects may result from the synergy between environmental exposures and genetic makeup. Results: The interaction between dioxin exposure in utero and specific genetic lesions disrupts embryonic eyelid closure. 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 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. We explored the genetic influences of dioxin exposure in the embryonic eyelid closure model and identified a novel gene-environment interaction mechanism in TCDD teratogenicity. Our data provide empirical evidence that specific pre-existing genetic conditions can increase the risk of adverse pregnancy outcomes of exposure to environmental agents
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