Methoxychlor metabolite HPTE alters viability and differentiation of embryonic thymocytes from C57BL/6 mice.
Methoxychlor metabolite HPTE alters viability and differentiation of embryonic thymocytes from C57BL/6 mice.
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DOI：
10.1080/1547691x.2018.1474978
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发表时间：
2018-12
影响因子：
3.3
通讯作者：
Broussard C
中科院分区：
文献类型：
--
作者：
Leung-Gurung L;Escalante Cobb P;Mourad F;Zambrano C;Muscato Z;Sanchez V;Godde K;Broussard C
内分泌干扰物（EDC）广泛存在于人造环境和自然环境中。公众对其潜在危险的认识日益提高，人们开始关注EDC及其代谢物是否具有显著的负面生物学效应。研究表明，EDC与滴滴涕和其他有机氯农药，如甲氧基氯（MXC）一样，对免疫细胞有不利影响，但没有研究涉及MXC的主要代谢物HPTE的影响。为了阐明HPTE不良反应的存在及其意义，本研究探讨了HPTE对免疫系统发育的一个关键窗口和组成部分——胚胎t细胞发育的影响。这一发育阶段的病变可导致终身免疫功能障碍，并增加自身免疫等免疫疾病的发病率。将C57BL/6小鼠胚胎胸腺细胞（GD 16-18）分别在0.005、0.05、0.5、5或50 μM HPTE或模型内分泌干扰物DES的作用下进行体外分化培养，模拟胸腺细胞发育的早期阶段。结果表明，与对照相比，HPTE和DES均可诱导胸腺细胞死亡。Annexin-V染色和程序性细胞死亡标志物Caspase 8显示，细胞的损失至少部分是由于诱导凋亡。此外，hpte诱导的细胞死亡不仅导致双阳性胸腺细胞的选择性丢失，还导致正在发育的CD4中间细胞（双阳性后部分分化胸腺细胞群）的丢失。胸腺细胞成熟（t细胞受体，TCR）和TCR连接（CD5）表面标记的表型分析显示，存活的胚胎胸腺细胞表达低水平的这两种标记。综上所述，这些数据表明，未成熟的胚胎胸腺细胞对HPTE暴露敏感，HPTE暴露的目标胸腺细胞群处于关键的分化步骤。这些发现表明HPTE可能在MXC暴露诱导的免疫功能障碍中起关键作用。
Endocrine-disrupting chemicals (EDC) are widespread in the built and natural environments. Heightened public awareness of their potential danger has led to concern about whether EDC and their metabolites have significant negative biological effects. Studies have shown that EDC like DDT and other organochlorine pesticides, such as methoxychlor (MXC), have adverse effects on immune cells, but no studies have addressed the impact of HPTE, the primary metabolite of MXC. To elucidate the presence and significance of HPTE adverse effects, this study explored the impact of HPTE on a critical window and component of immune system development, embryonic T-cell development. Lesions at this phase of development can lead to lifelong immune dysfunction and increased incidence of immune disease, such as autoimmunity. Embry-onic thymocytes (GD 16–18) from C57BL/6 mice were subjected to an in vitro differentiation culture that mimicked early steps in thymocyte development in the presence of 0.005, 0.05, 0.5, 5, or 50 μM HPTE, or a model endocrine disruptor, DES. The results indicated that compared to the vehicle control, HPTE and DES induced death of thymocytes. Annexin-V staining and Caspase 8, markers of programmed cell death, revealed that the loss of cells was due at least in part to induction of apoptosis. Moreover, HPTE-induced cell death not only resulted in selective loss of double positive thymocytes, but also loss of developing CD4 intermediate cells (post-double positive partially-differentiated thymocyte population). Phenotypic analysis of thymocyte maturation (T-cell receptor, TCR) and TCR ligation (CD5) surface markers revealed that surviving embryonic thymocytes expressed low levels of both. Taken together these data demonstrate that immature embryonic thymocytes are sensitive to HPTE exposure and that HPTE exposure targets thymocyte populations undergoing critical differentiation steps. These findings suggest HPTE may play a pivotal role in MXC exposure-induced immune dysfunction.