BACKGROUND Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. OBJECTIVES Herein, we sought to determine the molecular and cellular changes that occur in the colon in response to uranium bearing dust (UBD) exposure. METHODS Human colonoids from three biologically distinct donors were acutely exposed to UBD then digested for single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. Validation in colonoids was assessed using morphological and imaging techniques. RESULTS Human colonoids acutely exposed to UBD exhibited disrupted proliferation and hyperplastic differentiation of the secretory lineage cell, enteroendocrine cells (EEC). Single-cell RNA sequencing also showed more EEC subtypes present in UBD-exposed colonoids. DISCUSSION These findings highlight the significance of crypt-based proliferative cells and secretory cell differentiation using human colonoids to model major colonic responses to uranium-bearing particulate dust exposure. https://doi.org/10.1289/EHP13855.

中文翻译：

---

暴露于含铀粉尘的人类结肠的单细胞分析。


背景技术铀暴露仍然是一个重要的环境遗留问题和生理健康问题，位于美国西南部的数百个废弃铀矿在很大程度上影响着服务不足的土著社区。重金属对屏障通透性和抑制肠上皮愈合的负面影响已有描述；然而，肠上皮细胞内的转录组变化以及对谱系分化的影响在很大程度上尚不清楚。目的 在此，我们试图确定结肠中因接触含铀尘埃 (UBD) 而发生的分子和细胞变化。方法 将来自三个生物学上不同的供体的人类结肠急剧暴露于 UBD，然后消化进行单细胞 RNA 测序，以确定结肠上皮细胞特定身份发生的分子变化。使用形态学和成像技术评估类结肠中的验证。结果 急性暴露于 UBD 的人类结肠显示分泌谱系细胞、肠内分泌细胞 (EEC) 的增殖和增生性分化受到破坏。单细胞 RNA 测序还显示，暴露于 UBD 的结肠中存在更多 EEC 亚型。讨论这些发现强调了基于隐窝的增殖细胞和分泌细胞分化的重要性，使用人类结肠来模拟结肠对含铀颗粒粉尘暴露的主要反应。 https://doi.org/10.1289/EHP13855。