Mono-(2-ethylhexyl) phthalate induces NR4A subfamily and GIOT-1 gene expression, and suppresses CYP19 expression in human granulosa-like tumor cell line KGN.
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Ohno S, Yukinawa F, Noda M, Nakajin S
Mono-(2-ethylhexyl) phthalate induces NR4A subfamily and GIOT-1 gene expression, and suppresses CYP19 expression in human granulosa-like tumor cell line KGN.
Toxicol Lett. 2009 Dec 15;191(2-3):353-9. doi: 10.1016/j.toxlet.2009.10.004. Epub 2009 Oct 12.
- PubMed ID
- 19822197 [ View in PubMed]
- Abstract
The mechanism for transcriptional suppression of CYP19 by mono-ethylhexyl phthalate (MEHP) in a human ovarian granulosa cell line (KGN) was investigated. It is known that the CYP19 gene transcript in KGN cells predominantly includes exon PII among the 11 alternate exon I sequences. MEHP was found to significantly suppress Forskolin (FSK)-induced CYP19 gene transcription, CYP19 promoter II activity and CYP19 enzyme activity in a dose-dependent manner. Promoter assays using 5'-deleted promoter II reporter constructs suggested that the region important for responsiveness to MEHP exposure includes a putative CRE-like sequence and an SF-1 (NR5A1)/LRH-1 (NR5A2) binding sequence. Meanwhile, MEHP exposure rapidly and transiently induced nuclear receptor 4A (NR4A) mRNA, and gradually and continuously induced gonadotropin-inducible ovarian transcription factor-1 (GIOT-1; ZNF461) mRNA in KGN cells. The ectopic expression of NR4As and GIOT-1 suppressed promoter II activity, while among the NR4As expressed, only Nur77 (NR4A1) secondarily induced GIOT-1 mRNA expression. Based on these results, we believe that induction of the Nur77-GIOT-1 system by MEHP is involved in the transcriptional suppression of the CYP19 gene, and GIOT-1 may attenuate the promoter II activity due to suppression of SF-1 and/or LRH-1 transactivation in KGN cells.