As an important pollutant, perfluorooctane acid (PFOA) has been widely concerned and reported by thousands of times, while less is known about the concentration-response pathway of PFOA. The aim of the present work was to reveal the concentration-response mechanism of PFOA in human cells. Omics results showed that calcium-related pathways play key roles in PFOA injury mechanisms. The results of GO and KEGG analyses showed that the cAMP signaling pathway was presented as the top one in all of the regulatory patterns and concentrations groups of PFOA. In the cAMP signaling pathway, the adenosine A₁ receptor (ADORA1) recognized the low concentration of PFOA and induced pathway “G_i-cAMP-PKA” to decrease the concentration of cAMP. This indicated that the low concentration of PFOA may promote breast hyperplasia and inhibit lactation. While adenosine A_2A receptor (ADORA2A) recognized the high concentration of PFOA and induced pathway “G_S-AC-cAMP-RKA” to increase the concentration of cAMP, induce cell damage and may lead to the deterioration of breast cancer. The results of molecular dynamics simulation showed that PFOA could bind to ADORA1 and ADORA2A, thus cause subsequent signal transduction. Furthermore, considering the strong binding ability of PFOA with ADORA1, PFOA tends to bind to ADORA1 at a low concentration. On the other side, PFOA at high concentration will continue to bind to another receptor protein, ADORA2A, and activate subsequent signaling pathways. Combined analyses of transcriptomic and proteomic revealed that different concentrations of PFOA regulate cellular calcium-related pathways. The cAMP pathway showed a concentration-response effect of PFOA. After treatment with different concentrations of PFOA, ADORA1 and ADORA2A were activated respectively, showing opposite cellular effects, leading to kinds of breast lesions. In the nervous system, PFOA might induce a variety of nervous system diseases. The present work was an exploration on the toxicological mechanism of PFOA, providing important information on the health impacts of PFOA in humans.

全氟辛酸（PFOA）作为一种重要的污染物，已被广泛关注并被上千次报道，而对PFOA的浓度-响应途径却知之甚少。目前工作的目的是揭示全氟辛酸在人体细胞中的浓度反应机制。组学结果表明，钙相关通路在 PFOA 损伤机制中起关键作用。GO 和 KEGG 分析结果表明，cAMP 信号通路在 PFOA 的所有调节模式和浓度组中均处于首位。在 cAMP 信号通路中，腺苷 A ₁受体 (ADORA1) 识别低浓度的 PFOA 并诱导通路“G _i-cAMP-PKA”以降低 cAMP 的浓度。这说明低浓度的PFOA可能促进乳腺增生，抑制泌乳。而腺苷 A _2A受体 (ADORA2A) 识别出高浓度的 PFOA 并诱导通路“G _S-AC-cAMP-RKA”增加cAMP的浓度，诱导细胞损伤并可能导致乳腺癌恶化。分子动力学模拟结果表明，PFOA可以与ADORA1和ADORA2A结合，从而引起后续的信号转导。此外，考虑到 PFOA 与 ADORA1 的强结合能力，PFOA 倾向于在低浓度下与 ADORA1 结合。另一方面，高浓度的 PFOA 将继续与另一种受体蛋白 ADORA2A 结合，并激活随后的信号通路。转录组学和蛋白质组学的综合分析表明，不同浓度的全氟辛酸可调节细胞钙相关通路。cAMP 通路显示出 PFOA 的浓度反应效应。不同浓度PFOA处理后，ADORA1和ADORA2A分别被激活，显示出相反的细胞效应，导致各种乳房病变。在神经系统中，PFOA 可能诱发多种神经系统疾病。目前的工作是对全氟辛酸毒理学机制的探索，提供了关于全氟辛酸对人类健康影响的重要信息。