Bisphenol A-induced aromatase activation is mediated by cyclooxygenase-2 up-regulation in rat testicular Leydig cells.
Bisphenol A (4,4'-dihydroxy-2,2-diphenylpropane; BPA) is an endocrine disruptor that affects the reproductive health of wildlife and possibly of humans. Evidence suggests that BPA interrupts ovarian steroidogenesis by altering steroidogenic enzymes. We evaluated the effect of BPA on aromatase expression in rat testicular Leydig cells. In addition, we investigated whether cyclooxygenase-2 (COX-2) was involved in BPA-induced aromatase expression. BPA induced a time- and concentration-dependent increase in aromatase protein expression in rat testicular Leydig R2C cells. It also increased aromatase gene expression and its enzyme and promoter activity, but reduced testosterone synthesis; increased COX-2 mRNA expression and promoter activity, the production of prostaglandin E(2) (PGE(2)), and the gene expression of PGE(2) (EP2 and EP4) receptors; induced the activation of cyclic adenosine monophosphate (cAMP) response element (CRE) and CREB binding; and increased the phosphorylation of protein kinase A (PKA), Akt, and mitogen-activated protein (MAP) kinase signaling pathways. BPA activation of aromatase was reversed by various inhibitors (COX-2, PKA, Akt, ERK, JNK, and p38). Taken together, these results suggest that BPA increases aromatase activity, which is correlated with COX-2 up-regulation mediated by the CRE, PKA, Akt, and MAP kinase signaling pathways in rat testicular Leydig cells.
Kim
Ji Young
JY
College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju, South Korea.
Han
Eun Hee
EH
Kim
Hyung Gyun
HG
Oh
Kyo Nyeo
KN
Kim
Sang Kyum
SK
Lee
Kwang Yeol
KY
Jeong
Hye Gwang
HG
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001559:Benzhydryl Compounds; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007985:Leydig Cells / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000098826:Bisphenol A Compounds
D001141:Aromatase; D001559:Benzhydryl Compounds; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D020928:Mitogen-Activated Protein Kinases; D010636:Phenols; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; C006780:bisphenol A; D000098826:Bisphenol A Compounds