Connolly Jack C, Ishihara Yasuhiro, Sawaya Emma, Whitfield Valerie, Garrity Nicole, Sohata Rajveer, Tsymbal Mark, Lundberg Alyssa, La Merrill Michele A, DeWitt Jamie C, Ehrlich Allison K, Vogel Christoph F A
Center for Health and the Environment, University of California, Davis, CA, 95616, USA.
Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8521, Japan.
Cardiovasc Toxicol. 2025 Jul 29. doi: 10.1007/s12012-025-10048-w.
Epidemiological studies and in vivo animal models have shown that exposure to PFAS can lead to cardiovascular toxicity and promote atherosclerosis. In this study, we explored the effects of PFOA and PFOS exposure on lipid accumulation in macrophages and analyzed critical markers of foam cell formation, which are early precursors of atherosclerotic lesions. Our results demonstrate that PFOS and PFOA enhance lipid and cholesterol accumulation in human U937-derived macrophages, which is characteristic of foam cells. PFOS and PFOA induced the activity of the peroxisome proliferator-activated receptor gamma (PPARγ) and treatment with a PPARγ antagonist partly reversed the accumulation of lipids after PFAS exposure. Furthermore, the results show that PFOS and PFOA activate (NF)-erythroid-derived 2 (E2)-related factor 2 (Nrf2) and induce markers of oxidative stress. Gene expression analysis revealed that mRNA levels of interleukin-1β (IL-1β) and plasminogen activator inhibitor-2 (PAI-2) were upregulated in a time- and concentration-dependent manner in PFOS- and PFOA-treated macrophages. The expression of other key atherosclerosis-related enzymes, including cytochrome P450 8B1 (CYP8B1) and lanosterol synthase (LSS), was downregulated, whereas the expression of cyclooxygenase 2 (COX-2) and aldo-keto reductase family 1 member C3 (AKR1C3) was induced by PFOS and PFOA. Additionally, elevated levels of matrix metalloproteinases (MMP)-1 and MMP-12 were found in PFOS- and PFOA-treated cells, which were associated with increased cell migration. Furthermore, PFOS and PFOA enhanced the expression of IL-1β when macrophages were activated; however, elevated levels of IL-6 and COX-2 in activated macrophages were repressed by PFOS and PFOA. Together, the findings indicate that PFAS exposure modifies immune responses and promotes lipid accumulation in macrophages, potentially contributing to foam cell and plaque formation in atherosclerosis.
流行病学研究和体内动物模型表明，接触全氟辛烷磺酸会导致心血管毒性并促进动脉粥样硬化。在本研究中，我们探讨了全氟辛酸（PFOA）和全氟辛烷磺酸（PFOS）暴露对巨噬细胞脂质积累的影响，并分析了泡沫细胞形成的关键标志物，而泡沫细胞是动脉粥样硬化病变的早期前体。我们的结果表明，PFOS和PFOA会增强源自人U937的巨噬细胞中的脂质和胆固醇积累，这是泡沫细胞的特征。PFOS和PFOA诱导了过氧化物酶体增殖物激活受体γ（PPARγ）的活性，用PPARγ拮抗剂处理可部分逆转PFAS暴露后脂质的积累。此外，结果表明PFOS和PFOA激活了核因子红细胞2相关因子2（Nrf2）并诱导了氧化应激标志物。基因表达分析显示，在PFOS和PFOA处理的巨噬细胞中，白细胞介素-1β（IL-1β）和纤溶酶原激活物抑制剂-2（PAI-2）的mRNA水平呈时间和浓度依赖性上调。包括细胞色素P450 8B1（CYP8B1）和羊毛甾醇合酶（LSS）在内的其他关键动脉粥样硬化相关酶的表达下调，而环氧化酶2（COX-2）和醛酮还原酶家族1成员C3（AKR1C3）的表达则由PFOS和PFOA诱导。此外，在PFOS和PFOA处理的细胞中发现基质金属蛋白酶（MMP）-1和MMP-12水平升高，这与细胞迁移增加有关。此外，当巨噬细胞被激活时，PFOS和PFOA会增强IL-1β的表达；然而，PFOS和PFOA会抑制激活的巨噬细胞中IL-6和COX-2水平的升高。总之，这些发现表明，PFAS暴露会改变免疫反应并促进巨噬细胞中的脂质积累，可能导致动脉粥样硬化中泡沫细胞和斑块的形成。
