全氟烷基和多氟烷基物质(PFAS)是一类高度稳定的化学物质,广泛用于日常产品,在环境中广泛存在,即使是孕妇。虽然流行病学研究已将产前暴露于PFAS与儿童特应性皮炎联系起来,对它们对皮肤发育的毒性作用知之甚少,尤其是在胚胎期.在这项研究中,我们利用人类胚胎干细胞产生非神经外胚层(NNE)细胞,并将它们暴露于六个PFAS(全氟辛酸(PFOA),十一氟己酸(PFHxA),七氟丁酸(PFBA),全氟辛烷磺酸(PFOS),全氟己烷磺酸盐(PFHxS)和全氟丁酸(PFBS))在分化过程中评估其对早期皮肤发育的毒性。我们的结果表明,PFOS改变NNE细胞的纺锤体样形态为卵石样形态,破坏了几个NNE标记,包括KRT16、SMYD1和WISP1。6种PFAS通过破坏HED相关基因的表达水平而具有引起汗症外胚层发育不良(HED)的高潜力。转录组分析显示,在6个PFAS中,PFOS处理产生的差异表达基因(DEGs)数量最多(1156个),包括角质形成细胞相关基因KRT6A,KRT17、KRT18、KRT24、KRT40和KRT81。此外,我们发现,全氟辛烷磺酸治疗扰乱了几种参与调节皮肤细胞命运决定和分化的信号通路,包括TGF-β,NOTCH,刺猬,和河马信号通路。有趣的是,我们发现全氟辛烷磺酸抑制了,通过部分干扰细胞骨架相关基因的表达,NNE细胞的纤毛发生,这对于上述信号通路的细胞间转导至关重要。总的来说,我们的研究表明,PFAS可以抑制纤毛发生并阻碍重要信号通路的传导,潜在的先天性皮肤病。它揭示了早期胚胎皮肤发育毒性的潜在机制,并为PFAS的流行病学数据提供了解释。环境意义:我们采用基于人类胚胎干细胞的模型来证明全氟辛烷磺酸有可能增加多汗性外胚层发育不良的风险。这是通过针对纤毛来实现的,抑制纤毛生成,随后破坏了关键的信号通路,如TGF-β,缺口,刺猬,和河马,在胚胎皮肤发育的早期阶段。我们的研究强调了六种PFAS污染物对人类皮肤发育的危险和潜在影响。此外,我们强调密切考虑PFHxA的重要性,PFBA,PFHxS,和PFBS,因为他们已经显示出改变基因表达水平的能力,虽然程度较低。
Per- and polyfluoroalkyl substances (PFAS) are a class of highly stable chemicals, widely used in everyday products, and widespread in the environment, even in pregnant women. While epidemiological studies have linked prenatal exposure to PFAS with atopic dermatitis in children, little is known about their toxic effects on skin development, especially during the embryonic stage. In this study, we utilized human embryonic stem cells to generate non-neural ectoderm (NNE) cells and exposed them to six PFAS (perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid (PFBA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorobutyric acid (PFBS)) during the differentiation process to assess their toxicity to early skin development. Our results showed that PFOS altered the spindle-like morphology of NNE cells to a pebble-like morphology, and disrupted several NNE markers, including KRT16, SMYD1, and WISP1. The six PFAS had a high potential to cause hypohidrotic ectodermal dysplasia (HED) by disrupting the expression levels of HED-relevant genes. Transcriptomic analysis revealed that PFOS treatment produced the highest number (1156) of differentially expressed genes (DEGs) among the six PFAS, including the keratinocyte-related genes KRT6A, KRT17, KRT18, KRT24, KRT40, and KRT81. Additionally, we found that PFOS treatment disturbed several signaling pathways that are involved in regulating skin cell fate decisions and differentiation, including TGF-β, NOTCH, Hedgehog, and Hippo signaling pathways. Interestingly, we discovered that PFOS inhibited, by partially interfering with the expression of cytoskeleton-related genes, the
ciliogenesis of NNE cells, which is crucial for the intercellular transduction of the above-mentioned signaling pathways. Overall, our study suggests that PFAS can inhibit
ciliogenesis and hamper the transduction of important signaling pathways, leading potential congenital skin diseases. It sheds light on the underlying mechanisms of early embryonic skin developmental toxicity and provides an explanation for the epidemiological data on PFAS. ENVIRONMENTAL IMPLICATION: We employed a model based on human embryonic stem cells to demonstrate that PFOS has the potential to elevate the risk of hypohidrotic ectodermal dysplasia. This is achieved by targeting cilia, inhibiting
ciliogenesis, and subsequently disrupting crucial signaling pathways like TGF-β, NOTCH, Hedgehog, and Hippo, during the early phases of embryonic skin development. Our study highlights the dangers and potential impacts of six PFAS pollutants on human skin development. Additionally, we emphasize the importance of closely considering PFHxA, PFBA, PFHxS, and PFBS, as they have shown the capacity to modify gene expression levels, albeit to a lesser degree.