Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.
College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Chemosphere. 2024 Jul;359:142332. doi: 10.1016/j.chemosphere.2024.142332. Epub 2024 May 14.
Perfluorooctanesulfonic acid (PFOS) is a widely recognized environment pollutant known for its high bioaccumulation potential and a long elimination half-life. Several studies have shown that PFOS can alter multiple biological pathways and negatively affect human health. Considering the direct exposure to the gastrointestinal (GI) tract to environmental pollutants, PFOS can potentially disrupt intestinal homeostasis. However, there is limited knowledge about the effect of PFOS exposure on normal intestinal tissues, and its contribution to GI-associated diseases remains to be determined. In this study, we examined the effect of PFOS exposure on the gene expression profile of intestinal tissues of C57BL/6 mice using RNAseq analysis. We found that PFOS exposure in drinking water significantly downregulates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme, in intestinal tissues of mice. We found that diets containing the soluble fibers inulin and pectin, which are known to be protective against PFOS exposure, were ineffective in reversing the downregulation of HMGCS2 expression in vivo. Analysis of intestinal tissues also demonstrated that PFOS exposure leads to upregulation of proteins implicated in colorectal carcinogenesis, including β-catenin, c-MYC, mTOR and FASN. Consistent with the in vivo results, PFOS exposure leads to downregulation of HMGCS2 in mouse and human normal intestinal organoids in vitro. Furthermore, we show that shRNA-mediated knockdown of HMGCS2 in a human normal intestinal cell line resulted in increased cell proliferation and upregulation of key proliferation-associated proteins such as cyclin D, survivin, ERK1/2 and AKT, along with an increase in lipid accumulation. In summary, our results suggest that PFOS exposure may contribute to pathological changes in normal intestinal cells via downregulation of HMGCS2 expression and upregulation of pro-carcinogenic signaling pathways that may increase the risk of colorectal cancer development.
全氟辛烷磺酸（PFOS）是一种广泛认可的环境污染物，因其具有高生物蓄积潜力和长半衰期而备受关注。多项研究表明，PFOS 可以改变多种生物途径并对人类健康产生负面影响。考虑到环境污染物直接暴露于胃肠道（GI）道，PFOS 可能会破坏肠道内稳态。然而，对于 PFOS 暴露对正常肠道组织的影响及其对与 GI 相关疾病的贡献知之甚少。在这项研究中，我们使用 RNAseq 分析研究了 PFOS 暴露对 C57BL/6 小鼠肠道组织基因表达谱的影响。我们发现，饮用水中的 PFOS 暴露显著下调了肠道组织中的限速酮体生成酶 3-羟-3-甲基戊二酰辅酶 A 合酶 2（HMGCS2）。我们发现，含有可溶纤维菊糖和果胶的饮食虽然已知可预防 PFOS 暴露，但不能有效逆转体内 HMGCS2 表达的下调。对肠道组织的分析还表明，PFOS 暴露会导致与结直肠癌变相关的蛋白质表达上调，包括 β-连环蛋白、c-MYC、mTOR 和 FASN。与体内结果一致，PFOS 暴露导致体外培养的小鼠和人正常肠道类器官中 HMGCS2 的下调。此外，我们表明，在人正常肠道细胞系中通过 shRNA 介导的 HMGCS2 敲低导致细胞增殖增加和关键增殖相关蛋白（如 cyclin D、survivin、ERK1/2 和 AKT）的上调，同时脂质积累增加。总之，我们的结果表明，PFOS 暴露可能通过下调 HMGCS2 表达和上调致癌信号通路导致正常肠道细胞发生病理变化，从而增加结直肠癌发展的风险。
