Tissue-Dependent Induction of Heme Oxygenase-1 and Metallothionein-1/2 by Methyl Methanesulfonate

Abstract

-Methyl methanesulfonate (MMS), a methylating agent, is known to be a genotoxicant in testis. The purpose of this study was to investigate roles of oxidative stress-responsive proteins, heme oxygenase-1 (HO-1) and metallothionein-1/2 (MT-1/2), in genotoxicity of MMS. Cadmium, a potent genotoxicity inducer, induced HO-1 and MT-1/2 in rat livers and kidneys. Then we comparatively investigated MMS-induced HO-1 and MT-1/2 in rat livers, kidneys and testes. We found that a single administration of MMS (40 mg/kg) resulted in the induction of MT-1/2 mRNA in the liver, but not HO-1 mRNA, reaching maximum level at 6 hr and returning to the control levels by 24 hr. Interestingly, MMS induced both HO-1 and MT-1/2 mRNAs in the kidney. In contrast, MMS induced HO-1 mRNA, but not MT-1/2 mRNA in the testis. Since HO-1 and MT-1/2 have been recognized to respond to various oxidative stimuli, we further examined the inducing effect of MMS on these two proteins. MMS at dosages of 20 to 40 mg/kg for 2 consecutive weeks induced HO-1 mRNA (123 to 187% of the control) and protein (274 to 404% of the control) in rat testes. However, MT-1/2 mRNA was not induced by MMS administration, although a high level of expression was observed in comparison with the liver and kidney. These findings suggest that MMS induces HO-1 and/or MT-1/2 mRNA and its protein tissue-dependently, and the heme catabolites by HO-1 in the testis may contribute in some manner to its genotoxicity.

Mechanisms of cadmium-induced chronotoxicity in mice

“…Therefore, the basal (non-induced) level of hepatic MT is hard to think as a determination factor for Cd-induced chronotoxicity. Moreover, since MT is an inducible protein (Ashino et al, 2003;Haq et al, 2003) and its induction level after the injection is known to be important, we compared the MT induction pattern by the difference of injection times of Cd. As shown in Fig.…”

Embryonic mortality and intrauterine growth retardation (IUGR) associated with placental alterations in pregnant rats treated with methyl methanesulfonate (MMS) at the peri-implantation stage

“…Treatment of rats with MMS induces the synthesis of oxidative stress-responsive proteins (Ashino et al, 2003). In the present study, however, we treated female rats during the peri-implantation period, before the onset of formation of the chorioallantoic placenta.…”

Heat shock protein 32/heme oxygenase‐1 protects mouse Sertoli cells from hyperthermia‐induced apoptosis by CO activation of sGC signalling pathways

“…Reactions in the absence of these agents were used for control. Both heat shock and related stress factors, such as cadmium chloride (CdCl 2 ), increase Hsp32/ HO-1 expression in SCs (Kusakabe et al, 2008) and methyal methanesulfonate also raises expression in rat testes (Ashino et al, 2003). that impair SCs may disrupt spermatogenesis (Cheng and Mruk, 2002;Chen et al, 2008).…”

“…SCs are the primary site of action of heat and the only cells that abundantly express Hsp32/HO-1 in the seminiferous tubules of the testes (Ewing and Maines, 1995;Maines and Ewing, 1996;Setchell, 1998;Middendorff et al, 2000). Both heat shock and related stress factors, such as cadmium chloride (CdCl 2 ), increase Hsp32/ HO-1 expression in SCs (Kusakabe et al, 2008) and methyal methanesulfonate also raises expression in rat testes (Ashino et al, 2003). Although Hsp32/HO-1 in testis after hyperthermia or other treatments has been intensely investigated, the molecular mechanisms regarding the anti-apoptotic role of Hsp32/HO-1 are poorly understood.…”