Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure that is dependent on the mitogen-activated protein kinase kinase kinase 1 (MAP3K1). KO in mice results in defective eyelid closure and an autosomal recessive eye-open at birth phenotype. We have shown that exposure to dioxin, a persistent environmental toxicant, induces the same eye defect in heterozygous but not WT pups. Here, we explore the mechanisms of the (gene) and dioxin (environment) interactions (GxE) underlying defective eyelid closure. We show that, acting through the aryl hydrocarbon receptor, dioxin activates epidermal growth factor receptor signaling, which in turn depresses MAP3K1-dependent Jun N-terminal kinase (JNK) activity. The dioxin-mediated JNK repression is moderate but is exacerbated by heterozygosity. Therefore, dioxin exposed embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out or in eyelid epithelium attenuates the open-eye defects in dioxin-treated pups, whereas knockout of and that encodes the sphigosin-1-phosphate (S1P) receptors upstream of the MAP3K1-JNK pathway potentiates the dioxin toxicity. Our novel findings show that the crosstalk of aryl hydrocarbon receptor, epidermal growth factor receptor, and S1P-MAP3K1-JNK pathways determines the outcome of dioxin exposure. Thus, gene mutations targeting these pathways are potential risk factors for the toxicity of environmental chemicals.

中文翻译：

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MAP3K1 和 EGFR 信号传导的串扰介导阻碍发育组织闭合的基因-环境相互作用


信号转导途径的异常调节可能会对组织发育的生物过程产生不利影响。其中一个过程是胚胎眼睑闭合，它依赖于丝裂原激活的蛋白激酶激酶 1 (MAP3K1)。小鼠的 KO 导致眼睑闭合缺陷和常染色体隐性出生时睁眼表型。我们已经证明，接触二恶英（一种持久性环境毒物）会在杂合子幼崽中引起相同的眼睛缺陷，但在野生型幼崽中则不会。在这里，我们探讨了眼睑闭合缺陷的（基因）和二恶英（环境）相互作用（GxE）的机制。我们发现，二恶英通过芳基烃受体发挥作用，激活表皮生长因子受体信号传导，进而抑制 MAP3K1 依赖性 Jun N 末端激酶 (JNK) 活性。二恶英介导的 JNK 抑制是中等的，但杂合性会加剧。因此，暴露于二恶英的胚胎眼睑的JNK活性显着降低，上皮细胞分化加速并阻碍极化。敲除或敲除眼睑上皮可减轻二恶英治疗幼犬的睁眼缺陷，而敲除编码 MAP3K1-JNK 通路上游的 sphigosin-1-磷酸 (S1P) 受体的 和 会增强二恶英毒性。我们的新发现表明，芳烃受体、表皮生长因子受体和 S1P-MAP3K1-JNK 通路的串扰决定了二恶英暴露的结果。因此，针对这些途径的基因突变是环境化学物质毒性的潜在危险因素。