组织发育需要未成熟细胞类型通过基因程序分化为成熟、完全分化的细胞。发育过程中暴露于非诱变环境因素可能会增加癌症风险，但其潜在机制尚不清楚。我们使用了子宫内膜腺癌的小鼠模型来确定致病因素，该小鼠模型是由于在发育过程中短暂接触雌激素化学物质己烯雌酚（DES）而产生的。成人对照子宫的单细胞 RNA 测序 (scRNAseq) 和空间转录组学揭示了子宫上皮干细胞 (EpSC) 的新标记，鉴定了不同的管腔和腺体祖细胞 (PC) 群体，并定义了腺体和管腔上皮 (LE) 细胞分化轨迹。新生儿 DES 暴露破坏了子宫上皮细胞分化，导致无法产生 EpSC 群体或可区分的腺体和腔祖细胞或成熟细胞。相反，暴露于 DES 的上皮细胞的特征是单个增殖的 PC 群体和 Wnt/β-catenin 信号传导的广泛激活。潜在的子宫内膜基质细胞的炎症信号通路和氧化应激显着增加。这些变化共同激活了磷酸肌醇 3-激酶/AKT 丝氨酸-苏氨酸激酶信号传导以及以磷酸-AKT 和癌症相关蛋白 olfactomedin 4 为标志的细胞的恶性转化。在这里，我们定义了从发育暴露到内分泌的机制途径破坏化学物质对成人发病癌症的发展。这些发现解释了人类癌症（通常与 PI3K/AKT 信号传导的异常激活有关）如何可能因在发育过程中暴露于环境损害而导致。版权：这是一篇开放获取文章，不受任何版权保护，并且可能会任何人出于任何合法目的自由复制、分发、传播、修改、构建或以​​其他方式使用。该作品在知识共享 CC0 公共领域奉献下提供。

Tissue development entails genetically programmed differentiation of immature cell types to mature, fully differentiated cells. Exposure during development to non-mutagenic environmental factors can contribute to cancer risk, but the underlying mechanisms are not understood. We used a mouse model of endometrial adenocarcinoma that results from brief developmental exposure to an estrogenic chemical, diethylstilbestrol (DES), to determine causative factors. Single-cell RNA sequencing (scRNAseq) and spatial transcriptomics of adult control uteri revealed novel markers of uterine epithelial stem cells (EpSCs), identified distinct luminal and glandular progenitor cell (PC) populations, and defined glandular and luminal epithelium (LE) cell differentiation trajectories. Neonatal DES exposure disrupted uterine epithelial cell differentiation, resulting in a failure to generate an EpSC population or distinguishable glandular and luminal progenitors or mature cells. Instead, the DES-exposed epithelial cells were characterized by a single proliferating PC population and widespread activation of Wnt/β-catenin signaling. The underlying endometrial stromal cells had dramatic increases in inflammatory signaling pathways and oxidative stress. Together, these changes activated phosphoinositide 3-kinase/AKT serine-threonine kinase signaling and malignant transformation of cells that were marked by phospho-AKT and the cancer-associated protein olfactomedin 4. Here, we defined a mechanistic pathway from developmental exposure to an endocrine disrupting chemical to the development of adult-onset cancer. These findings provide an explanation for how human cancers, which are often associated with abnormal activation of PI3K/AKT signaling, could result from exposure to environmental insults during development.Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.