title: Oxidative stress and phthalate-induced down-regulation of steroidogenesis in MA-10 Leydig cells.
abstract: Previous studies have shown that phthalate exposure can suppress steroidogenesis. However, the affected components of the steroidogenic pathway, and the mechanisms involved, remain uncertain. We show that incubating MA-10 Leydig cells with mono-(2-ethylhexyl) phthalate (MEHP) resulted in reductions in luteinizing hormone (LH)-stimulated cAMP and progesterone productions. cAMP did not decrease in response to MEHP when the cells were incubated with cholera toxin or forskolin. Incubation of MEHP-treated cells with dibutyryl-cAMP, 22-hydroxycholesterol or pregnenolone inhibited the reductions in progesterone. Increased levels of reactive oxygen species (ROS) occurred in response to MEHP. In cells in which intracellular glutathione was depleted by buthionine sulfoximine pretreatment, the increases in ROS and decreases in progesterone in response to MEHP treatment were exacerbated. These results indicate that MEHP inhibits MA-10 Leydig cell steroidogenesis by targeting LH-stimulated cAMP production and cholesterol transport, and that a likely mechanism by which MEHP acts is through increased oxidative stress.
authors: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States.
authors: Liang
authors: L
authors: Zhou
authors: Matthew C
authors: MC
authors: Beattie
authors: Chieh-Yin
authors: CY
authors: Lin
authors: June
authors: J
authors: Liu
authors: Kassim
authors: K
authors: Traore
authors: Vassilios
authors: V
authors: Papadopoulos
authors: Barry R
authors: BR
authors: Zirkin
authors: Haolin
authors: H
authors: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000633:toxicity; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011374:Progesterone / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D011374:Progesterone; D007986:Luteinizing Hormone; D004051:Diethylhexyl Phthalate; D000242:Cyclic AMP; C016599:mono-(2-ethylhexyl)phthalate; D005978:Glutathione
keywords: 22-hydroxycholesterol; 22HC; 2′,7′-dichlorodihydrofluorescein diacetate; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; BSO; DCF; DEHP; GSH; Gsα; IBMX; LH; Leydig cell; MEHP; MTT; Oxidative stress; P5; Phthalate; ROS; STAR; Steroidogenesis; dbcAMP; di-(2-ethylhexyl) phthalate; dibutyryl cAMP; glutathione; isobutyl-methylxanthine; l-buthionine-sulfoximine; luteinizing hormone; mono-(2-ethylhexyl) phthalate; pregnenolone; reactive oxygen species; steroidogenic acute regulatory protein; stimulatory G protein α subunit
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