Abstract：
Chronic exposure to arsenic (As) promotes skin carcinogenesis in humans and potentially disturbs resident stem cell dynamics, particularly during maternal and early life exposure. In the present study, we demonstrate how only prenatal arsenic exposure disturbs keratinocyte stem cell (KSC) conditioning using a BALB/c mice model. Prenatal As exposure alters the normal stemness (CD34, KRT5), differentiation (Involucrin), and proliferation (PCNA) program in skin of offspring with progression of age as observed at 2, 10, and 18 weeks. Primary KSCs isolated from exposed animal at Day-2 showed increased survival (Bax:Bcl-xL, TUNEL assay), proliferation (BrdU), and differentiation (KRT5, Involucrin) potential through the activation of pro-carcinogenic IGF2R-MAPK cascade (IGF2R-G(α)q-MEK1-ERK1/2). This was associated with reduced enrichment of histone H3K27me3 and its methylase, EZH2 along with increased binding of demethylase, KDM6A at Igf2r promoter. Altered KSCs conditioning through disturbed Igf2r imprint contributed to impaired proliferation and differentiation and an aggravated tumor response in offspring.
摘要：
长期暴露于砷（As）会促进人类皮肤癌变，并可能干扰常驻干细胞动力学，特别是在母亲和生命早期暴露期间。在本研究中,我们使用BALB/c小鼠模型证明了仅产前砷暴露会干扰角质形成细胞干细胞（KSC）调节。产前暴露改变了正常的干性(CD34，KRT5)，分化（卷起蛋白），在2、10和18周时观察到后代皮肤的增殖（PCNA）程序，随着年龄的增长。在第2天从暴露的动物中分离的原代KSC显示出增加的存活率（Bax：Bcl-xL，TUNEL测定)，增殖（BrdU），通过激活促致癌IGF2R-MAPK级联（IGF2R-G（α）q-MEK1-ERK1/2）和分化（KRT5，Involucrin）潜力。这与组蛋白H3K27me3及其甲基化酶的富集减少有关，EZH2与去甲基酶的结合增加，KDM6A在Igf2r启动子。通过受干扰的Igf2r印迹改变KSCs调节导致后代的增殖和分化受损以及肿瘤反应加重。
