PFOA regulate adenosine receptors and downstream concentration-response cAMP-PKA pathway revealed by integrated omics and molecular dynamics analyses

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 “Gi-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 A2A receptor (ADORA2A) recognized the high concentration of PFOA and induced pathway “GS-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.