Bisphenol-A reduces DNA methylation after metabolic activation

<jats:title>Abstract</jats:title><jats:p>Bisphenol-A (BPA) is an important environmental contaminant with adverse health effects suspected to be mediated through epigenetic mechanisms. We had reported that the FLO1-dependent flocculation of transgenic yeast expressing human DNA methyltransferase (<jats:italic>DNMT</jats:italic> yeast) is a useful tool in epigenotoxicology studies. In this report, we have investigated the effects of BPA in the presence of metabolic activation (S-9 mix) on the transcription level of the <jats:italic>FLO1</jats:italic> gene in the <jats:italic>DNMT</jats:italic> yeast. In the presence of metabolic activation, BPA inhibited the intensity of green fluorescence reporter protein (GFP) driven by the <jats:italic>FLO1</jats:italic> promoter. A metabolite of BPA, 4-methyl-2,4-bis(p-hydroxyphenyl) pent-1-ene (MBP), also exhibited similar inhibitory effect. Furthermore, BPA in the presence of S-9 mix had only a weak while MBP had no inhibitory effects on the expression of modified GFP reporter gene under the control of <jats:italic>FLO1</jats:italic> promoter with reduced CpG motifs. Aforementioned behavior was confirmed by the inhibition of flocculation as well as <jats:italic>FLO1</jats:italic> gene mRNA expression. In addition, the global DNA methylation level in the human HEK293 cells was also reduced by MBP. These results indicate that BPA metabolites have inhibitory effect on DNA methylation. Our approach offers a novel <jats:italic>in vitro</jats:italic> method for screening for chemicals that can alter the epigenome by a mechanism dependent on their metabolic activation.</jats:p>