title: A chromatin modifier regulates Sertoli cell response to mono-(2-ethylhexyl) phthalate (MEHP) via tissue inhibitor of metalloproteinase 2 (TIMP2) signaling.
abstract: Epigenetic silencing mechanisms are essential for regulating germ cell apoptosis in response to different stimuli during complicated spermatogenesis. Herein, we report the potential signaling events related to up-regulation of metastasis associated protein 1 (Mta1), a master chromatin modifier, during mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cells (SCs) injury. Mta1 up-regulation correlated to the gradual increases of MYC expression in MEHP-treated SCs. Selective knockdown of MYC abolished MEHP-induced activation of Mta1, suggesting that MYC may regulate the Mta1 signaling following MEHP injury. Furthermore, MTA1 acted as a specific corepressor of tissue inhibitor of metalloproteinase 2 (Timp2) during SCs injury. Mta1 repressed Timp2 expression either directly by recruiting histone deacetylase 2 onto the Timp2 promoter or indirectly by enhancing NF-κB-mediated inflammatory responses during MEHP injury. This transcriptional and post-translational down-regulation of Timp2/TIMP2 expression consequently resulted in the stimulated activation of matrix metalloproteinase 2 (MMP2) in SCs, which should ultimately promote germ cell death upon MEHP insult. From a functional standpoint, inhibition of endogenous Mta1 expression along with anti-inflammation treatment in cultured SCs could rescue MEHP-inhibited TIMP2 and subsequently rebalanced MMP2 activity to the control level. Together with the recently reported essential role of TIMP2/MMP2 signaling in MEHP-induced specific disruption of junctional complexes in the seminiferous epithelium, our results further substantiate a critical role of Mta1 in the control of SCs response to MEHP stimulation. The MYC/Mta1/TIMP2 circuit may serve as an important scavenger mechanism to help to maintain the capacity of damaged SCs to support germ cell development following MEHP injury.
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an 710032, China; Department of General Surgery, 3rd Hospital of PLA, No. 45 Dongfeng Road, Bao Ji 721004, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, 3rd Hospital of PLA, No. 45 Dongfeng Road, Bao Ji 721004, China.
authors.forename: Jun-Hao
authors.initials: JH
authors.lastname: Lai
authors.affiliation: Department of Blood Transfusion, 3rd Hospital of PLA, No. 45 Dongfeng Road, Bao Ji 721004, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an 710032, China. Electronic address: liweipepeyato@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016259:Genes, myc / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D002843:Chromatin; C503336:Mta1 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate
keywords: Histone deacetylase 2 (HDAC2); Metastasis associated protein 1 (Mta1); Mono-(2-ethylhexyl) phthalate (MEHP); Nucleosome remodeling and histone deacetylase (NuRD) complex; Sertoli cells (SCs); Tissue inhibitor of metalloproteinase 2 (TIMP2)