Perfluorooctanoic acid (PFOA) exposure inhibits DNA methyltransferase activities and alters constitutive heterochromatin organization

Perfluorooctanoic acid (PFOA) is a persistent and widespread industry-made chemical. Emerging evidence indicates that PFOA exposure could be meditated through DNA methylation, yet, the molecular mechanisms governing the epigenetic states have not been well established. In this study, we investigated the epigenetic alterations and inhibitory mechanisms upon PFOA exposure by identifying changes related to DNA methyltransferase (DNMT) with fluorescence correlation spectroscopy and stimulated emission depletion nanoscopy in human breast epithelial cells (MCF7). PFOA exposure at 100 and 200 μM altered the mobility of DNMT3A and inhibited the enzymatic activity of DNMT, resulting in global DNA demethylation. Moreover, PFOA significantly altered the heterochromatin organization, as noted by the distribution profile of histone 3 lysine 9 tri-methylation (H3K9me3) at 200 and 400 μM exposure levels with super-resolution microscopy. An increased redistribution around the periphery of the nucleus was noted with a more diffused distribution beyond the 200 μM exposure. Overall, exposure of PFOA resulted in DNA demethylation accompanied by altered expression patterns of DNMT1 and DNMT3A. These findings provided new insights on the epigenetic alterations and revealed an altered heterochromatin packaging upon exposure to PFOA, implicating a mechanistic mode of action of DNA demethylation through direct impacts on DNMTs and increasing susceptibility to diseases such as cancer.