Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferators-activated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats.
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.
Ryu
Ju Young
JY
College of Pharmacy, Pusan National University, Pusan, Republic of Korea.
Whang
Jung
J
Park
Hyeyoung
H
Im
Ji Young
JY
Kim
Jeonga
J
Ahn
Mee Young
MY
Lee
Jaewon
J
Kim
Hyung Sik
HS
Lee
Byung Mu
BM
Yoo
Sun Dong
SD
Kwack
Seung Jun
SJ
Oh
Jae Ho
JH
Park
Kui Lea
KL
Han
Soon Young
SY
Kim
Seung Hee
SH
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
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