Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development.
Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development.
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DOI：
10.1016/j.taap.2009.09.023
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发表时间：
2010-01-15
影响因子：
3.8
通讯作者：
Barnett JB
中科院分区：
文献类型：
--
作者：
Hanson ML;Brundage KM;Schafer R;Tou JC;Barnett JB
镉(Cd)既是一种环境污染物，也是香烟烟雾的一种成分。尽管有证据表明，成人接触Cd会引起免疫系统的变化，但关于产前接触Cd对免疫调节作用的文献报道有限。Sonic Hedgehog(Shh)和Wnt/β-Catenin通路是胸腺细胞成熟所必需的。一些研究表明，镉暴露会影响不同器官系统中的这些途径。本研究旨在研究孕期镉暴露对胸腺细胞发育的影响，并确定这些影响是否与Shh和Wnt/β-Catenin通路的失调有关。怀孕的C57BL/6小鼠在整个怀孕期间暴露于与环境相关的剂量(10ppm)的Cd，并在出生当天评估对胸腺的影响。用流式细胞仪检测胸腺细胞表型。用Gli：荧光素酶报告细胞系检测Shh信号。用实时定量RT-PCR和Western印迹分别检测两条信号通路中靶基因的转录和关键成分的翻译。孕期接触Cd可增加孕妇外周血中的CD4+细胞和双阴性细胞亚群(DN4、CD44、CD25)的数量。Shh和Wnt/β-catenin信号在胸腺中均减少。目的基因Shh(Patched1和Gli1)和Wnt/β-catenin(c-fos和c-myc)在胸腺细胞亚群之间受到不同程度的影响。这些发现表明，出生前接触Cd会扰乱胸腺中的两条信号通路，导致胸腺细胞发育改变。
Cadmium (Cd) is both an environmental pollutant as well as a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/β-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/β-catenin pathways. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways was assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4+ cells and a subpopulation of double-negative cells (DN; CD4-CD8-), DN4 (CD44-CD25-). Shh and Wnt/β-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/β-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.
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