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Di (2-ethylhexyl) phthalate (DEHP) inhibits steroidogenesis and induces mitochondria-ROS mediated apoptosis in rat ovarian granulosa cells

Abstract

Increased oxidative stress (OS) due to ubiquitous exposure of Di (2-ethylhexyl) phthalate (DEHP) can affect the quality of oocyte by inducing apoptosis and hampering granulosa cell mediated steroidogenesis. The present study was carried out to investigate whether DEHP induced OS affect the steroidogenesis and induce apoptosis in rat ovarian granulosa cells. OS was induced by exposing granulosa cells with various concentrations of DEHP (0.0, 100, 200, 400 and 800 μM) for 72 h in vitro. Intracellular reactive oxygen species (ROS), oxidative stress (OS), mitochondrial membrane potential, cellular senescence, apoptosis, steroid hormones (estradiol & progesterone) and gene expression were analyzed. The results showed that effective dose of DEHP (400 µg) significantly increased OS by elevating ROS level, mitochondrial membrane potential, β-galactosidase activity with higher mRNA expression levels of apoptotic genes (Bax, Cytochrome-C and Caspase3) and lower level of anti-apoptotic gene (Bcl2) as compared to control. Further, DEHP significantly (P>0.05) decreased the level of steroid hormones (estradiol and progesterone) in conditioned medium and this effect was reciprocated with lower expression (P>0.05) of steroidogenic responsive genes (Cyp11a1, Cyp19A1, Star, ERβ1) in treated granulosa cells. Furthermore, co-treatment with N-Acetyl-Cysteine (NAC) rescues the effects of DEHP on OS, ROS, β-galactosidase levels and gene expression activities. Together, these results suggest that DEHP induces oxidative stress via ROS generation and inhibited steroid synthesis via modulating steroidogenic responsive genes which leads to the induction of apoptosis through activation of Bax/Bcl-2-cytochrome-c, caspase3-mediated mitochondrial apoptotic pathway in rat granulosa cells.

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Publication details

The article was received on 03 Oct 2018, accepted on 04 Feb 2019 and first published on 04 Feb 2019


Article type: Paper
DOI: 10.1039/C8TX00263K
Citation: Toxicol. Res., 2019, Accepted Manuscript

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    Di (2-ethylhexyl) phthalate (DEHP) inhibits steroidogenesis and induces mitochondria-ROS mediated apoptosis in rat ovarian granulosa cells

    A. Tripathi, V. Pandey, A. Sahu, A. Singh and P. Dubey, Toxicol. Res., 2019, Accepted Manuscript , DOI: 10.1039/C8TX00263K

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