Diethyl phthalate (DEP) works as a phthalate plasticizer and is ubiquitously used in personal care products, cosmetics, medical equipment and pharmaceutical coating. DEP is considered a potential endocrine disruptor. Previously we found DEP-enhanced apoptosis induced by serum deprivation in PC12 cells. However, the relationship between DEP and longevity-related factors, sirtuins and epigenetic factors (e.g. DNA methyltransferases) remains unclear, because genome modification caused by chemical toxicity, sirtuins and epigenetic factors have played key roles in abnormal metabolism and development. Here, we investigate whether DEP affects sirtuins (SIRT1 and SIRT2) and methyltranferases (DNMT1 and DNMT3a) on the apoptosis of PC12 cells. We found that DNMT3a was significantly decreased by serum deprivation. However, DNMT3a, DNMT3b and SIRT1 were significantly increased under the enhancement of apoptosis induced by serum deprivation. These results suggest that SIRT1, DNMT3a and DNMT3b play multiple and complex roles in different apoptotic stages. Our results showed DEP triggered epigenetic factors on PC12 cells apoptosis under nutrition stress. Finally, our results suggest that monitoring epigenetic factors such as DNMT3a, DNMT3b and SIRT1 could be a useful tool for chemical toxicity risk assessment. Copyright © 2012 John Wiley & Sons, Ltd.