Bisphenol A (BPA) and its substitute fluorene-9-bisphenol (BHPF) are used in consumer products; however, their toxic effects on intestinal epithelium remain largely unknown. In this study, we combined intestinal organoids and single-cell RNA sequencing to investigate the impact of BPA and BHPF exposure on intestinal cell composition, differentiation, and function. Both compounds inhibited the growth of small intestinal organoids, with BHPF exhibiting a more potent inhibitory effect. BPA and BHPF did not significantly alter the overall cell type composition; however, they led to different alterations in cell–cell communications. Gene Ontology enrichment analysis showed that BPA and BHPF exposures affected various biological processes, such as glutathione transferase activity, antioxidant activity, and lipid metabolism, in cell type-specific and compound-dependent manners. Trajectory analysis demonstrated that BPA and BHPF altered the differentiation trajectory of the intestinal cells. To further connect the cellular mechanism to the phenotypic impact in vivo, we constructed a mouse model exposed to BPA or BHPF and observed significant alterations in intestinal morphology, including reduced crypt depth and villus length and impaired stem cell proliferation and self-renewal. These results provide novel insights into the cell type-specific effects of BPA and BHPF on the intestinal epithelium and highlight the potential risks of exposure to these compounds. Our findings underscore the importance of evaluating the safety of BPA substitutes and contribute to a better understanding of the effects of environmental chemicals on gut health.

中文翻译：

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双酚A及其替代品芴-9-双酚对肠道稳态的异质性影响


双酚A（BPA）及其替代品9-芴双酚（BHPF）用于消费品；然而，它们对肠上皮的毒性作用仍然很大程度上未知。在本研究中，我们结合肠道类器官和单细胞 RNA 测序来研究 BPA 和 BHPF 暴露对肠道细胞组成、分化和功能的影响。两种化合物均抑制小肠类器官的生长，其中 BHPF 表现出更有效的抑制作用。 BPA 和 BHPF 没有显着改变总体细胞类型组成；然而，它们导致了细胞间通讯的不同改变。基因本体富集分析表明，BPA 和 BHPF 暴露以细胞类型特异性和化合物依赖性方式影响各种生物过程，例如谷胱甘肽转移酶活性、抗氧化活性和脂质代谢。轨迹分析表明 BPA 和 BHPF 改变了肠细胞的分化轨迹。为了进一步将细胞机制与体内表型影响联系起来，我们构建了暴露于 BPA 或 BHPF 的小鼠模型，并观察到肠道形态的显着变化，包括隐窝深度和绒毛长度减少以及干细胞增殖和自我更新受损。这些结果为 BPA 和 BHPF 对肠上皮的细胞类型特异性影响提供了新的见解，并强调了暴露于这些化合物的潜在风险。我们的研究结果强调了评估 BPA 替代品安全性的重要性，并有助于更好地了解环境化学物质对肠道健康的影响。