Endocrine disrupter bisphenol a induces orphan nuclear receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells.
The orphan nuclear receptor Nur77 (NR4A1) is a member of the nuclear receptor superfamily, which plays an important role in the regulation of LH-mediated steroidogenesis in testicular Leydig cells. The aim of the current study was to investigate the potential role of bisphenol A (BPA) on orphan nuclear receptor Nur77 gene expression and steroidogenesis. Northern blot analysis demonstrated that BPA transiently induced Nur77 mRNA expression, and protein kinase inhibitor H-89 and PD98059 strongly inhibited the induction of BPA-mediated Nur77 gene expression in mouse Leydig tumor cell line, K28. Moreover, BPA increased the activation of mitogen-activated protein kinase. Transient transfection assay demonstrated that BPA increased Nur77 gene promoter activity and Nur77 transactivation, whereas BPA did not significantly affect the interaction of Nur77 with its corepressor. Furthermore, BPA increased progesterone biosynthesis in K28 cells, which was suppressed by overexpression of dominant negative Nur77. Finally, BPA injection to prepubertal mice revealed that the expression of Nur77 mRNA was elevated, and this induction was correlated with increased concentration of testicular T in vivo. Taken together, these results demonstrated that BPA induces Nur77 gene expression and subsequently alters the steroidogenesis in testicular Leydig cells. These observations provide a novel mechanism by which BPA acts as an endocrine disrupting chemical.
Song
Kwang-Hoon
KH
Hormone Research Center, Chonnam National University, Kwangju 500-757, Republic of Korea.
Lee
Keesook
K
Choi
Hueng-Sik
HS
D000818:Animals; D001559:Benzhydryl Compounds; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects; D007202:Indicators and Reagents; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D011863:Radioimmunoassay; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000096:biosynthesis*; D013737:Testis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D004968:Estrogens, Non-Steroidal; D007202:Indicators and Reagents; D020928:Mitogen-Activated Protein Kinases; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013256:Steroids; D014157:Transcription Factors; D001616:beta-Galactosidase; C539818:Nr4a1 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds