title: Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferators-activated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats.
abstract: Di(2-ethylhexyl) phthalate (DEHP) is a well-known hepatic and reproductive toxicant whose toxicity may be mediated by peroxisome proliferators-activated receptor (PPAR). This study examined the effects of DEHP on the expression of PPAR-regulated genes involved in testicular cells apoptosis. Sprague-Dawley male rats were treated orally with 250, 500, or 750 mg/kg/d DEHP for 28 d, while control rats were given corn oil. The levels of cell cycle regulators (pRb, cyclins, CDKs, and p21) and apoptosis-related proteins were analyzed by Western blot analysis. The role of PPAR-gamma (PPAR-gamma), class B scavenger receptor type 1 (SR-B1), and ERK1/2 was further studied to examine the signaling pathway for DEHP-induced apoptosis. Results showed that the levels of pRB, cyclin D, CDK2, cyclin E, and CDK4 were significantly lower in rats given 500 and 750 mg/kg/d DEHP, while levels of p21 were significantly higher in rat testes. Dose-dependent increases in PPAR-gamma and RXRalpha proteins were observed in testes after DEHP exposure, while there was a significant decrease in RXRgamma protein levels. In addition to PPAR-gamma, DEHP also significantly increased SR-B1 mRNA and phosphorylated ERK1/2 protein levels. Furthermore, DEHP treatment induced pro-caspase-3 and cleavage of its substrate protein, poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner. Data suggest that DEHP exposure may induce the expression of apoptosis-related genes in testes through induction of PPAR-gamma and activation of the ERK1/2 pathway.
authors.affiliation: College of Pharmacy, Pusan National University, Pusan, Republic of Korea.
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Ryu
authors.forename: Jung
authors.initials: J
authors.lastname: Whang
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Park
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Im
authors.forename: Jeonga
authors.initials: J
authors.lastname: Kim
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Ahn
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Byung Mu
authors.initials: BM
authors.lastname: Lee
authors.forename: Sun Dong
authors.initials: SD
authors.lastname: Yoo
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kwack
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Oh
authors.forename: Kui Lea
authors.initials: KL
authors.lastname: Park
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Han
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D004051:Diethylhexyl Phthalate / Q000494:pharmacology / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010969:Plastics / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051122:Scavenger Receptors, Class B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D047495:PPAR gamma; D010969:Plastics; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D004051:Diethylhexyl Phthalate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3