Exposure to di-(2-ethylhexyl) phthalate reduces secretion of GDNF via interfering with estrogen pathway and downregulating ERK/c-fos signaling pathway in astrocytes

Di-(2-ethylhexyl) phthalate (DEHP) is a typical endocrine-disrupting chemical (EDC) that can increase the risk of central nervous system disease. This study aimed to investigate the in vitro and in vivo effects of DEHP exposure on GDNF secretion and the underlying mechanisms. Pregnant Wistar rats were randomly assigned into four groups and administered 0, 30, 300, or 750 mg/kg DEHP daily by oral gavage. In addition, primary astrocytes were exposed to mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP. Our results showed that DEHP exposure reduced GDNF levels and downregulated the ERK/c-fos signaling pathway in the cerebral cortex of male, but not female, offspring. Moreover, exogenous estrogen could overcome the decreased GDNF levels in astrocytes caused by MEHP exposure. MEHP also decreased p300 levels and downregulated the ERK/c-fos signaling pathway in primary astrocytes. Honokiol restored GDNF levels following MEHP exposure by activating the ERK/c-fos signaling pathway, while the inhibitor U0126 further reduced the GDNF levels. These results suggested that DEHP exposure could interfere with the normal effects of estrogen in the brain and downregulate the ERK/c-fos signaling pathway to decrease the GDNF secretion from astrocytes in the cerebral cortex.