Many chemicals accumulate in organisms through a variety of different mechanisms. Cationic amphiphilic drugs (CADs) accumulate in lysosomes and bind to membranes causing phospholipidosis, whereas many lipophilic chemicals target adipose tissue. Perfluoroalkyl substances (PFASs) are widely used as surfactants, but many of them are highly bioaccumulating and persistent in the environment, making them notorious environmental toxicants. Understanding the mechanisms of their bioaccumulation is, therefore, important for their regulation and substitution with new, less harmful chemicals.

We compared the highly bioaccumulative perfluorooctanesulfonic acid PFOS to its three less bioaccumulative alternatives perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutane sulfonic acid (PFBS), in their ability to accumulate and remain in lung epithelial cells (NCI-H292) and adipocytes (3T3-L1K) in vitro. As a reference point we tested a set of cationic amphiphilic drugs (CADs), known to highly accumulate in cells and strongly bind to phospholipids, together with their respective non-CAD controls. Finally, all compounds were examined for their ability to bind to neutral lipids and phospholipids in cell-free systems.

Cellular accumulation and retention of the test compounds were highly correlated between the lung epithelial cells and adipocytes. Interestingly, although an anion itself, intensities of PFOS accumulation and retention in cells were comparable to those of CAD compounds, but PFOS failed to induce phospholipidosis or alter lysosomal volume.

Compared to other lipophilicity measures, phospholipophilicity shows the highest correlation (Rˆ2 = 0.75) to cellular accumulation data in both cell types and best distinguishes between high and low accumulating compounds. This indicates that binding to phospholipids may be the most important component in driving high cellular accumulation in lung epithelial cells, as well as in adipocytes, and for both CADs and bioaccumulating PFASs. Obtained continuous PLS models based on compound's affinity for phospholipids and neutral lipids can be used as good prediction models of cellular accumulation and retention of PFASs and CADs.

许多化学物质通过各种不同的机制在生物体内积累。阳离子两亲药物（CAD）积累在溶酶体中，并结合到膜上，引起磷脂变性，而许多亲脂性化学物质则靶向脂肪组织。全氟烷基物质（PFASs）被广泛用作表面活性剂，但其中许多具有很高的生物蓄积性，并且在环境中具有持久性，使其成为臭名昭著的环境毒物。因此，了解它们的生物蓄积机理对于它们的监管和用危害程度较小的新化学物质替代十分重要。

我们将高生物蓄积性全氟辛烷磺酸PFOS与三种生物蓄积性较低的替代品全氟辛酸（PFOA），全氟己酸（PFHxA）和全氟丁烷磺酸（PFBS）的蓄积能力和保留在肺上皮细胞（NCI-H292）和体外脂肪细胞（3T3-L1K）。作为参考，我们测试了一组阳离子两亲药物（CAD），已知它们在细胞中高度积聚并与磷脂牢固结合，并分别具有各自的非CAD对照。最后，检查了所有化合物在无细胞系统中与中性脂质和磷脂结合的能力。

在肺上皮细胞和脂肪细胞之间，测试化合物的细胞积累和保留高度相关。有趣的是，尽管阴离子本身，但PFOS在细胞中的积累和保留强度与CAD化合物相当，但PFOS无法诱导磷脂变性或溶酶体体积改变。

与其他亲脂性测度相比，亲脂性在两种细胞类型中均与细胞蓄积数据具有最高的相关性（Rˆ2 = 0.75），并且可以最佳地区分高蓄积化合物和低蓄积化合物。这表明与磷脂的结合可能是驱动肺上皮细胞，脂肪细胞以及CAD和生物蓄积PFAS的高细胞蓄积最重要的组成部分。基于化合物对磷脂和中性脂质的亲和力获得的连续PLS模型可以用作PFAS和CAD的细胞蓄积和保留的良好预测模型。