Di-(2-ethylhexyl) Phthalate Upregulates ATF3 Expression and Suppresses Apoptosis in Mouse Genital Tubercle

Abstract

Objectives: To investigate the effect of di-(2-ethylhexyl) phthalate (DEHP) on the expression of activating transcription factor 3 (ATF3) and apoptosis of fetal mouse genital tubercle (GT). Methods: In this developmental toxicity study, pregnant C57BL/6 mice were exposed to corn oil or DEHP (100 or 500 mg/kg/day) from embryonic day 12 (ED12) to ED16. Apoptosis was characterized by Terminal transferase dUTP nick end labeling (TUNEL) assay. Using RT-PCR and western blot, the expressions of ATF3 and apoptosis-related genes (P53, Bcl-2 and Bax) were investigated. Results: Apoptosis of fetal mouse GT cells notably decreased after DEHP treatment. DEHP activated ATF3 both at the mRNA and protein levels in GT. Furthermore, pro-apoptotic P53 was downregulated and the ratio of anti-apoptotic (Bcl-2)/pro-apoptotic (Bax) was not significantly changed. Conclusions: These results suggest that DEHP may induce external genital defects via a mechanism involving apoptosis, which might correlate with the regulation of ATF3 and P53 expressions.