title: Bisphenol A-induced aromatase activation is mediated by cyclooxygenase-2 up-regulation in rat testicular Leydig cells.
abstract: 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.
authors.affiliation: College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju, South Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Han
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.forename: Kyo Nyeo
authors.initials: KN
authors.lastname: Oh
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.forename: Kwang Yeol
authors.initials: KY
authors.lastname: Lee
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: 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
chemical_list: 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