* Graduate School of Pharmaceutical Sciences, Graduate School of Agriculture, Hokkaido University, Sapporo 060-0812, Japan, and
CREST, Japan Science, Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
1 To whom correspondence should be addressed at Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, 060-0812, Japan. Fax: 81117064988; E-mail: hiro{at}pharm.hokudai.ac.jp.
Received June 3, 2005; accepted August 8, 2005
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ABSTRACT |
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Key Words: bisphenol A; reactive oxygen species; DJ-1; cell death; oxidative stress; mitochondria.
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INTRODUCTION |
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Reactive oxygen species (ROS), including superoxide hydrogen peroxide (H2O2), and hydroxyl radical (HO), damage various cell components such as unsaturated lipids, proteins, and nucleic acids. Oxidative stress is caused by ROS in cells in which large amounts of ROS are produced by alternative activities of scavenger proteins or by dysfunction of the mitochondrial respiratory chain pathway with reduction of complex I activity. Complex I (NADH:ubiquinone oxidoreductase) catalyses the first step in the mitochondrial electron transport chain, by which electrons from the oxidation of NADH are used to convert oxygen to water, the energy liberated being trapped in ATP formation and ultimately used as the body's energy source. Oxidation of nucleic acid, lipid, and protein is thought to result in the onset of various diseases, including cancer, infertility, and neurodegenerative diseases such as PD (Agarwal et al., 2003
; Benhar et al., 2002
; Golden et al., 2002
; Rego and Oliveira, 2003
). Expression of DJ-1 and oxidation of DJ-1 have been shown to be induced in cells that had been administered ROS-inducing chemicals (Kinumi et al., 2004
; Mitsumoto et al., 2001
; Mitsumoto and Nakagawa, 2001
), and abnormal oxidative forms of DJ-1 have been found in some patients with sporadic forms of PD (Bandopadhyay et al., 2004
). We and other groups have shown that some DJ-1 is located in mitochondria in addition to the cytoplasm and nucleus (Shendelman et al., 2004
; Shinbo et al., 2005a
; Zhang et al., 2005
) and that translocation of DJ-1 to mitochondria was stimulation by oxidative stress (Blackinton et al., 2005
; Jin et al., 2005
; Li et al., in press
). Precise functions of DJ-1 in mitochondria are, however, not clear.
In addition to its transcriptional activity as a coactivator, we previously reported that DJ-1 plays a role in the anti-oxidative stress reaction, in which reactive oxygen species were eliminated in vitro and in vivo by oxidizing DJ-1 itself, and that mutations of DJ-1, including various mutations found in PD patients, lead to oxidative stress-induced cell death (Taira et al., 2004b; Yokota et al., 2003
). Other groups also reported anti-oxidative activity of DJ-1 (Canet-Aviles et al., 2004
; Martinat et al., 2004
; Shendelman et al., 2004
). It has been shown that, of three cysteines at amino acid numbers 46, 53, and 106 in DJ-1, C106 was first oxidized by addition of SO3H or SO2H, followed by oxidation of C46 and C53 with a dose of H2O2 added to cultured cells (Kinumi et al., 2004
), and that C106 was required for DJ-1 to exert activity against oxidative stress (Canet-Aviles et al., 2004
; Martinat et al., 2004
; Shendelman et al., 2004
; Taira et al., 2004b; Takahashi-Niki et al., 2004
). In addition to oxidation of DJ-1, DJ-1 has been reported to be conjugated with SUMO-1 on a lysine residue at amino-acid number 130 (K130) (Shinbo et al., in press
). Sumoylation of DJ-1 at K130 has been found to essential for DJ-1 to exert its full activities, including activities for ras-dependent transformation, cell growth stimulation, and anti-oxidative stress (Shinbo et al., in press
). Loss of these functions of DJ-1 is therefore thought to lead to the onset of PD.
Some endocrine disruptors (EDs) such as lindane, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and bisphenol A (BPA) have been shown to induce oxidative stress in the brain, liver, kidney, testis, and epididymal sperm in rodents (Bindhumol et al., 2003; Chitra et al., 2003
; Junqueira et al., 1988
; Kabuto et al., 2003
, 2004
; Latchoumycandane et al., 2002
; Stohs et al., 1991
). Furthermore, BPA and some bisphenols have been reported to reduce mitochondrial function (Nakagawa and Toyama, 2000
), but the precise mechanisms underlying these phenomena have not been elucidated.
In this study, we analyzed the effect of DJ-1 on BPA-induced cell death. The results showed that BPA induced oxidative stress in mitochondria and that DJ-1 plays a role as a scavenger of ROS to prevent cell death.
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MATERIALS AND METHODS |
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Cells and treatment.
Mouse Neuro2a and GC1 cells were purchased from American Tissue Culture Collection. All the cells used in this study were cultured in Dulbecco's modified medium supplemented with 10% calf serum. Cells were then administered various concentrations of BPA dissolved in dimethyl sulfoxide (DMSO) for 24 or 48 h. As a vehicle control, 0.1% DMSO was added to the medium.
Western blotting and isoelectric focusing.
Proteins were prepared from whole tissues or cultured cells for Western blot analysis as follows. The brain and sperm were homogenized in 20 mM phosphate buffer (pH 7.5) containing 150 mM NaCl, 1% NP-40, 1 mM EDTA, 1 mM PMSF, and protease inhibitors. Cultured cells were homogenized in a buffer containing 20 mM TrisHCl (pH 7.5), 150 mM NaCl, 1% NP-40, 5 mM EDTA, 1 mM PMSF, and protease inhibitors. Extracts were then centrifuged at 12,000 rpm for 5 min, and their supernatants were used. To analyze proteins in mitochondria by Western blotting, cells were homogenized in a buffer containing 0.25 M sucrose, 10 mM TrisHCl (pH 7.3), and 1 mM EDTA and then centrifuged at 1000 x g for 10 min. Their supernatant fractions were then centrifuged at 12,000 x g for 15 min, and the pellet fractions (mitochondrial-enriched fractions) were suspended in a buffer containing 0.25 M sucrose, 10 mM TrisHCl (pH 7.3), 10 mM KCl, 1.5 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, and 0.1 mM PMSF. Concentration of mitochondria protein was measured by using a BCA protein assay kit (PERBIO), and 20 µg of mitochondria protein was used for Western blotting. For isoelectric focusing, cells were homogenized in PBS containing 2% NP-40 and centrifuged at 12,000 rpm for 5 min, and their supernatants were used. Proteins in these extracts were then separated in a 12.5% polyacrylamide gel containing SDS or in an isoelectric focusing gel of pH 58, transferred onto nitrocellulose membranes, and reacted with an anti-DJ-1 antibody, which was an affinity-purified rabbit anti-DJ-1 polyclonal antibody described previously (Nagakubo et al., 1997), an anti-complex I monoclonal antibody cocktail (Mito Science), or an anti-actin antibody (Chemicon). The proteins on the membranes were then reacted with IRDye800- or Alexa Fluor680-conjugated secondary antibodies followed by visualization using an infrared imaging system (Odyssey, LI-COR).
Flow cytometric analysis.
Nero2a and GC1 cells were mixed with 10 µM 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) (Molecular Probes) or 2-[6-( 4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF) (Daiichi Kagaku) in Hank's solution containing 10 mM HEPES-KOH (pH 7.4) for 30 min in the dark, and their fluorescences were measured using a FACScan flow cytometer (Becton-Dickinson) with excitation at 488 and emission at 530 nm. The amounts of fluorescences were also quantified using a "CELL QUEST" program as a value of "median".
Indirect immunofluorescence.
Cells were mixed with 500 nM MitoTracker-Green (Molecular Probes) for 40 min and then reacted with 5 µM MitoSOX Red (Molecular Probes) for 10 min. The cells were then fixed with a solution containing 4% paraformaldehyde and reacted with an affinity-purified rabbit anti-DJ-1 polyclonal antibody. The cells were then reacted with a Cy-5-conjugated anti-rabbit IgG and observed under a confocal laser fluorescent microscope.
siRNA.
The nucleotide sequences for siRNAs targeting DJ-1 were 5'-CCUUGCUAGUAGAAUAAACdTdT-3' and 3'-dTdTGGAACGAUCAUCUUAUUUG-5' for upper and lower strands, respectively. siRNA-targeting luciferase was purchased from Greiner (Japan). Twenty nM siRNA was transfected into cells using Lipofectamine 2000 (Invitrogen) according to the supplier's manual.
Complex I activity.
A mitochondria-enriched fraction was prepared as described above. Seventy µg of mitochondria protein and 0.05 mM ubiquinone 1 were added to 35 mM phosphate buffer (pH 7.4) containing 2.65 mM sodium cyanide, 5 mM MgCl2, 1 mM EDTA, 1 mg/ml bovine serum albumin, and 2 µg/ml antimycin in a final volume of 0.48 ml. After incubation of the mixture at 37°C for 2 min, 0.02 ml of 5 mM NADH solution was added to the reaction mixture, and decrease in absorbance was measured by a spectrophotometer at 340 nm for 4 min.
Cell viability assay.
Cell viability was measured by a methyl thiazolyl tetrazolium (MTT) assay using a cell counting kit 8 (DOJINDO).
Statistical analyses.
Data are expressed as means ± SD. Statistical analyses were performed using analysis of variance (one-way ANOVA) followed by unpaired Student's t-test.
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RESULTS |
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Proteins were extracted from Neuro2a and GC1 cells at various times after administration of BPA, separated on isoelectric focusing gels, and analyzed by blotting with an anti-DJ-1 antibody (Figs. 4A and 4B, upper panels). The same aliquots of proteins on filters were also reacted with an anti-actin antibody to show loading controls, and intensities of bands were measured by an infrared imaging system (Figs. 4A and 4B in lower panels, 4C and 4D). The results showed that the amounts of oxidized DJ-1 in both Neuro2a and Gc1 cells increased with BPA administration in time- and dose-dependent manners (Figs. 4A and 4B). The rate of oxidized DJ-1/unoxidized DJ-1 was significantly increased at 48 h after administration of 50 µM BPA in Neuro2a cells and at 24 h after administration of 100 µM BPA in GC1 cells (Figs. 4C and 4D), indicating that BPA stimulates oxidization of DJ-1 in Neuro2a and GC1 cells.
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Dysfunction of Mitochondrial Complex 1 in Cells Induced by BPA Administration
Dysfunction of mitochondria is thought to be responsible for the onset of neurodegenerative disorders, including PD, and DJ-1 is a causative gene of familial PD. Dysfunction of mitochondrial complex 1 has been found in PD patients, and rats or mice that had been administered drugs that injure mitochondrial complex 1 have been reported to show PD-like phenotypes, including dopaminergic neuronal cell death (see recent reviews, Corti et al., 2005; Shen and Cookson, 2004
; Tretter et al., 2004
). Moreover, since we have found that BPA induced production of ROS in the mitochondria of Neuro2a and GC1 cells and injured the mitochondria, activity and expression levels of subunits of mitochondorial complex 1 were examined. Neuro2a and GC1 cells were administered various concentrations of BPA. At 48 h after administration, mitochondria-rich fractions were prepared, and their activities and expression levels of subunits of complex 1, including subunits of 39, 30, and 20 kDa, were analyzed by Western blotting with anti-complex 1 subunit antibodies (Fig. 6). The expression of DJ-1 in mitochondrial-rich fractions was also examined. While the expression levels of all of the subunits of mitochondrial complex 1 decreased with BPA administration in a dose-dependent manner, complex I activity level was found to increase in Neuro2a cells or to hardly change in GC1 cells at low concentrations of BPA and then to significantly decrease in a dose-dependent manner at high concentrations of BPA (decrease at more than 50 and 100 µM BPA in Neuro2a and GC1 cells, respectively) (Figs. 2, 6A6D). It is notable that patterns of complex 1 activities, initial increase and then decrease, paralleled those of DJ-1 expression in cells (Figs. 6E and 6F). To assess the relationship between DJ-1 expression and complex 1 activity, siRNA targeting the DJ-1 or luciferase gene, which is a nonspecific control, was transfected into Neuro2a and GC1 cells to knock down expression of the respective gene, and activities of complex 1 were measured at 3 days after transfection. Introduction of these siRNAs into cells was confirmed not to affect the expressions of subunits of complex 1 (Figs. 6C and 6D). Although siRNA against luciferase affected neither the expression of DJ-1 nor the activity of complex 1, siRNA against DJ-1 reduced both the expression level of DJ-1 and activity level of complex 1 to 10% and 70% of those without siRNA in Neuro2a and GC1 cells, respectively (Figs. 6E and 6F, lanes 79). These results suggest that BPA abrogates complex I activity by disrupting complex 1 and that DJ-1-knockdown decreases complex I activity without decrease in complex I expression. The results also suggest that the initial increase in the level of DJ-1 expression upon BPA administration that leads to ROS production plays a role in maintenance of complex 1 activity.
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DISCUSSION |
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In this study, we examined the expression and oxidative levels of DJ-1 after administration of BPA to mice and cultured cells, and we found that expression of DJ-1 was induced by BPA-induced ROS production concomitant with oxidation of DJ-1. We also found that BPA compromised mitochondria, resulting in reduction of the activity of mitochondrial complex 1 and that upon injury of mitochondria by BPA, an elevated expression level DJ-1 was observed on the injured mitochondria to restore the activity of complex 1. Since DJ-1 was located in the cytoplasm, nucleus, and mitochondria in various types of cells (Bandopadhyay et al., 2004; Nagakubo et al., 1997
; Shendelman et al., 2004
; Shinbo et al., 2005a
, in press
; Wagenfeld et al., 2000
; Zhang et al., 2005
), and some DJ-1 was translocated to mitochondria after oxidative stress (Blackinton et al., 2005
; Jin et al., 2005
; Li et al., 2005
), the localization of DJ-1 in mitochondria in the cells that had been administered BPA was thought to affect BPA-induced ROS production.
The activity of DJ-1 to sustain the activity of complex 1 was, however, observed at 50 and 100 µM BPA in Neuro2a and GC1 cells, respectively, and this activity was lost over these concentrations. Since, at high concentrations of BPA, cells began to die and the amount of DJ-1 also decreased, it is thought that the amount of DJ-1 is not sufficient to sustain the activity of complex 1. Alternatively, although DJ-1 contains three cysteines, and oxidation of a cysteine at amino acid number 106 (C106) is essential for DJ-1 to exert its anti-oxidative stress activity (Taira et al., 2004b; Takahashi-Niki et al., 2004
), oxidation of all three cysteines by excess ROS, which is produced by high doses of BPA, for instance, may result in loss of its activity (Kinumi et al., 2004
; Taira et al., 2004b
).
Although DJ-1 is an abundant protein and approximately 5 x 105 molecules/cell of DJ-1 is present in cells, it is likely that, in addition to DJ-1, other ROS-scavenging proteins such as superoxide dismutase, glutathione peroxidase and catalase, and proteins belonging to other redox systems participate in protecting cells from BPA-induced cell injury. We have found that drastic changes in expressions of genes, including genes related to stress, apoptosis, oxidative stress, and neurotoxicity, occurred in DJ-1 knockdown and that expressions of some genes were regulated by DJ-1 (Nishinaga et al., in press), suggesting that in addition to anti-oxidative activity of DJ-1, transcriptional function of DJ-1 toward genes related to stress functions is important.
In this study, levels of ROS production peaked at 12 h after BPA administration in GC1 cells and then decreased at 24 and 48 h. ROS production in Neuro2A cells, however, continued to occur during these periods. In the kidney, liver, and testis, an isoform of UDP-glucuronosyltransferase (UGTs) has been shown to metabolize BPA to BPA-glucuronide (Reinhechel et al., 1995). Although the presence of UGTs in GC1 cells has not been examined, BPA produced at 12 h after BPA administration might be metabolized in GC1 cells.
The present study showed that BPA induced production of various ROS, including highly reactive hydroxy radicals, and ROS have been shown to attack mitochondrial complex I (Yokota et al., 1999). Nakagawa and Toyama reported reduction of complex 1 activity after incubation of a mitochondria-rich fraction with BPA in vitro, but degradation of mitochondria and production of ROS were not examined (Nakagawa and Toyama, 2000
). Since the present study showed that BPA induces ROS production and inhibits complex I activity by disrupting complex I, it would be interesting to examine whether degradation of complex 1 by BPA also occurs in vitro using an electron microscopy and whether this degradation is restored by DJ-1.
Environmental factors are thought to trigger the onset of PD. Several neurotoxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTT), rotenone, 6-hydroxydopamine (6-OHDA), and a metabolite of dopamine itself, have been reported to injure mitochondria, resulting in dopaminergic neuron death (Jenner, 2003). Recently, BPA has been reported to affect movement and to induce dopaminergic neuron death when BPA was administered to embryonal mice and into the substantia nigra of adult rats, respectively, though ROS levels were not examined (Kabuto et al., 2004
; Mizuo et al., 2004
; Suzuki et al., 2003
). BPA has been detected in several tissues and the blood serum of humans (Ikezuki et al., 2002
; Schonfelder et al., 2002
) and accumulates in adipose tissue and membranes, creating the potential for long-term exposure of humans to a low dose of BPA. Human exposure to PBA, and our resent results, suggest that BPA could be a risk factor for the onset of familial and sporadic PD. Furthermore, there are many factors in the environment that cause oxidative stress to humans, including smoking, UV light, alcohol, and environmental contaminants. These factors, including BPA, might act by themselves or in combination as risk factors for diseases such as cancer, infertility, and neurodegenerative diseases.
Since the activity of mitochondrial complex I was significantly diminished by siRNA targeting DJ-1 in the cells of this study, it is possible that DJ-1 has a novel function to maintain complex I activity. In DJ-1-knockdown cells, complex 1 was still intact. Although the precise molecular basis of this reaction is not clear at present, it is important to clarify its mechanism.
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ACKNOWLEDGMENTS |
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