Life Sciences 100 (2014) 61–66

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Effects of sub-chronic aluminum chloride exposure on rat ovaries Fu Y. a,1, Jia F.B. b,1, Wang J. a, Song M. a, Liu S.M. c, Li Y.F. a,⁎, Liu S.Z. d, Bu Q.W. e a

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China Veterinary and Animal Husbandry Department, Liaoning Agricultural College, Liaoning 115009, China c School of Animal Biology, The University of Western Australia, 35 Stirling Highway Crawley, WA 6009, Australia d Weike Biotechnology Development Company, Harbin 150069, China e Veterinary Health And Epidemic Prevention Station, The Forest Industry Region of Heilongjiang, Harbin 150008, China b

a r t i c l e

i n f o

Article history: Received 10 November 2013 Accepted 29 January 2014 Available online 13 February 2014 Keywords: Trace minerals Energy supply Ovary Reproduction function Female rats

a b s t r a c t Aims: This experiment investigated the effects of sub-chronic aluminum chloride (AlCl3) exposure on rat ovaries. Main methods: Eighty female Wistar (5 weeks old) rats, weighed 110–120 g, were randomly divided into four treatment groups: control group (CG), low-dose group (LG, 64 mg/kg BW AlCl3), mid-dose group (MG, 128 mg/kg BW AlCl3) and high-dose group (HG, 256 mg/kg BW AlCl3). The AlCl3 was administered in drinking water for 120 days. The ovarian ultrastructure was observed. The activities of acid phosphatase (ACP), alkaline phosphatase (ALP), succinate dehydrogenase (SDH), Na+–K+-ATPase, Mg2+-ATPase and Ca2+-ATPase, the contents of Fe, Cu and Zn, and the protein expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in the ovary were determined. Key findings: The results showed that the structure of the ovary was disrupted, the activities of ALP, ACP, SDH, Na+–K+-ATPase, Mg2+-ATPase and Ca2+-ATPase, the contents of Zn, Fe and the protein expression of FSHR and LHR were lowered, and the content of Cu was increased in AlCl3-treated rats than those in control. Significance: The results indicate that sub-chronic AlCl3 exposure caused the damage of the ovarian structure, the disturbed metabolism of Fe, Zn and Cu and the decreased activities of Na+–K+-ATPase, Mg2+-ATPase and Ca2+-ATPase in the ovary, which could result in suppressed energy supply in the ovary. A combination of suppression of energy supply and reduction of expression of FSHR and LHR could inhibit ovulation and corpus luteum development, leading to infertility in female rats. © 2014 Elsevier Inc. All rights reserved.

Introduction Biological effects of aluminum (Al) are linked to the development of dialysis dementia, osteomalacia, Alzheimer's disease, and Parkinson's disease. Our previous researches have shown that AlCl3 caused toxic effects on the brain, bone, immune, and hematopoietic system (Gu et al., 2009; Li et al., 2011; Zhu et al., 2011; Zhang et al., 2011). Toxicity to the reproductive system of Al has also drawn great attention worldwide recently. Among these researches, most of them focus on the male reproductive system (Yousef et al., 2007; Sun et al., 2011; Ige and Akhigbe, 2012), while a few reports are about the female reproductive system. In female mice, Al accumulates in the ovary which could damage the ovarian structure (Chinoy and Patel, 2001). However, Al causes a transient disturbance to oestrous cycle regularity in female rats, but does not develop into reproductive toxicity (Agarwal et al., 1996). Sakr et al. (2010) reported an excess of congenital anomalies in ⁎ Corresponding author. Tel.: +86 13936574268; fax: +86 451 55191672. E-mail address: [email protected] (Y.F. Li). 1 Both authors contributed equally to this study; Northeast Agricultural University and Liaoning Agricultural College contributed equally to this study. 0024-3205/© 2014 Elsevier Inc. All rights reserved.

women workers at an Al smelter compared with their previous employment periods without access to Al, and demonstrated that Al exposure has detrimental effects on the reproductive system. In many developing countries, infertility is an important health issue (Esmaeilzadeh et al., 2013). A recent population-based-survey across many countries estimated the prevalence of infertility to be 9% on average, with a range of 3.5% to 16.7%, and female infertility is higher than that of the male (Boivin et al., 2007). Causes to infertility are multifactorial. Ovulatory disorders caused by disturbed hormone profiles and damaged ovary structure can lead to infertility (Kuohung et al., 2011). Trif et al. (2008) found that Al level was high in the ovarian and uterine tubes of adult female rats administrated orally with Al sulfate, and the tissue levels were correlated to the Al dosages. Shen et al. (1999) observed that Al nitrate at concentrations of 30 mg/L and 60 mg/L in the medium inhibited the viability and meiotic maturation of cultured mouse oocyte. Agarwal et al. (1996) found that the offspring of gestation rats treated with Al lactate disturbed oestrous cycle regularity. Wang et al. (2011) suggested that Al exposure disturbed the secretory function of the ovary, and reduced the levels of FSH and LH in the rat serum. These evidences demonstrate that Al is a potential risk to female infertility.


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Materials and methods

then transferred into a triangle flask, added with 4 mL nitric acid and 1 mL perchloric acid, and kept overnight. The mixture was heated slowly till it became colorlessly transparent. After cooling at room temperature, the sample was transferred into a 5 mL volumetric flask, and the volume was made up to 5 mL with 0.5% nitric acid. The sample was protected from light during the process. The absorbency of the solution was read in a flame atomic absorption spectrophotometer (HP 3510 atomic absorption spectrophotometer). The Zn, Cu and Fe standard solutions were prepared in 0.5% nitric acid for the derivation of the calibration curves for each element. The wavelengths were respectively set for recording Zn, Fe and Cu at 213.9 nm, 248.3 nm and 324.7 nm.


Determination of enzyme activity in the ovary

Eighty healthy female Wistar rats (5 weeks old), weighed 110– 120 g, were randomly allocated into four groups. All the rats were acclimatized for one week, and then AlCl3 was orally administered in drinking water for 120 days. The concentrations of AlCl3 in drinking water were 0 (control group, CG), 0.4 g/L (low-dose, LG), 0.8 g/L (mid-dose, MG) and 1.2 g/L (high-dose, HG), respectively. The water consumption of the individual rats averaged at 18 mL/d with a range from 16 to 19 mL/d, resulting in the doses of AlCl3 at 64 (1/20 LD50), 128 (1/10 LD 50 ), and 256 (1/5 LD 50) mg/kg BW AlCl 3 respectively for LG, MG, and HG groups. The doses of this experiment were determined according to the LD50 of AlCl3 · 6H2O (1283.60 mg/kg). All rats had free access to fresh water and housed in cages at temperatures of 22–25 °C and relative humidity at 55 ± 5%, ventilation frequency at 18 times/h and a 12-h light/dark cycle. The rats were kept in plastic cages (five rats per cage) with soft chip bedding. The size of the cages was 470 × 300 × 150 mm3, which was adequate for accommodating five rats. Throughout the experiment, wood chips were renewed every third day and rats were given drinking water and food ad libitum. The health state of rats was monitored daily and the body weight was recorded monthly.

The activities of ALP, ACP, SDH, Na+–K+-ATPase, Mg2+-ATPase and Ca2+-ATPase in the ovary were determined using 125I radioimmunoassay kits (New Bay Biological Technology Co. Ltd., Tianjin, China), following the procedure of the kit introduction.

We hypothesize that aluminum chloride (AlCl3) can damage the ovary, leading to female infertility. We used a rat model to investigate the effects of oral administration of AlCl3 on the ovary. In the experiment, the morphology of the ovary, the contents of trace elements (Fe, Cu and Zn), the activities of acid phosphatase (ACP), alkaline phosphatase (ALP), succinate dehydrogenase (SDH), Na+–K+-ATPase, Mg 2 + -ATPase and Ca 2 + -ATPase, and the expression of folliclestimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in the ovary were determined to depict the basic toxicological mechanisms of AlCl3 on the functions of the ovary.

Sample collection The use of the animals and the study protocol was approved by the Ethics Committee on the Use and Care of Animals, Northeast Agricultural University (Harbin, China). After they were administered with AlCl3 for 120 days, the rats were anesthetized with ether. The ovary was collected, and 0.1 g of the ovary sample was weighed and homogenized in ice bath for detecting the enzyme activities. An ovary tissue sample about 1.0 × 1.0 × 2.0 mm3 size was put into 10% formaldehyde fluid for the detection of FSHR and LHR. And 1.0 × 1.0 × 1.0 mm3 ovary tissue was put into 2.5% glutaraldehyde solution for the observation of the ovarian morphology. The remaining ovary tissue was stored at −70 °C for the determination of Fe, Zn and Cu concentrations. The detection of the ovarian morphology The ovarian samples were fixed in 2.5% glutaraldehyde solution for 72 h. The samples were embedded in Spurr's resin by using Leica/LKB Embedding Capsules Easy Molds. Ultrathin sections with an average thickness of 70 nm were sectioned with a Reichert Ultracut equipped with a diamond knife, stained with uranyl acetate and lead citrate, and examined under a JEOL JEM-1230 electron microscope which was operated at 80 kV. A picture by model lesion was taken. This method proceeded according to Yamada et al. (2014). Determination of Fe, Zn and Cu levels in the ovary The levels of Zn, Fe and Cu in the ovary were determined in flame atomic absorption spectrophotometry by Zhu et al. (2011). The ovary was quantified to 0.1 g and dried at 80 °C for 12 h. The sample was

Determination of FSHR and LHR expressions in the ovary FSHR and LHR expressions were determined by immunohistochemistry (Guo et al., 2005). The fixed ovary sample was embedded with paraffin, and then stained with FSHR/LHR immunohistochemistry kits (Beijing Biosynthesis Biotechnology Co. Ltd., Beijing, China/Wuhan Biosynthesis Biotechnology Co. Ltd., Wuhan, China). After deparaffinage, sections in 0.01 M citrate buffer solution (pH 6.0) were placed in microwave oven for 20 min to unmask the FSHR/LHR protein. The sections were incubated with endogenous peroxide blocking solution (0.3% H2O2) at 37 °C for 30 min. Thereafter, the sections were incubated for 30 min with serum taken from a rabbit which was not immunized by the target protein. This kind of protein would eliminate a false positive reaction. The samples were subsequently incubated with a rabbit antirat FSHR/LHR polyclonal antibody in 1:200 PBS (pH 7.4) at 4 °C overnight. Then the samples reacted with the biotin-conjugated second antibody and streptavidin-peroxidase solution for 1 h at room temperature, and a diaminobenzidine (DAB) solution was added to stain the FSHR/LHR protein. The average gray scale was measured using Motic image 3.2 micrograph analysis software (Motic, German), which was applied to quantitate the nuclear FSHR/LHR levels. The average gray scale was negatively correlated with the expression of FSHR/LHR protein. The sections were observed under a microscope (model: BA 400, Motic, German). Statistical analysis The results were expressed as least square mean ± standard deviation (SD) and analyzed by one-way analysis of variance using the statistical package SPSS 16.0 for Windows (SPSS Inc., Chicago, IL, USA). P b 0.05 was considered a significant difference and P b 0.01 was a markedly significant difference. Results Ultrastructure of the ovary The nuclear chromatin, the nuclear envelope, rough endoplasmic reticulum and the structure of mitochondria of the ovary are shown in Fig. 1 for CG, and Fig. 2 for HG. There were obvious damages on the nuclear and cytoplasm in HG. The margination and concentration of nuclear chromatin (Fig. 2B-1, C-1 and D-1) show the apoptosis of the ovary granulosa cells (Fig. 2B-a). The nuclear envelope structure is irregular (Fig. 2D-4). The mitochondria are swollen, the cristae are disintegrated and vacuolated (Fig. 2B-2, C-2 and E-2), the rough endoplasmic reticulum is dilated and loses ribosomes (Fig. 2D-3), and the Golgi body

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3 1


4 Fig. 3. The contents of Fe, Cu, and Zn in ovaries of rats administrated with AlCl3 in drinking water for 120 days. CG control group, LG low-dose group, MG mid-dose group, HG highdose group. *P b 0.05, **P b 0.01 versus control group.

A Fig. 1. Electron microscopy image (A): ovarian tissue of rats in CG (×16,500). 1: nuclear chromatin; 2: mitochondria; 3: rough endoplasmic reticulum; 4: nuclear envelope.

structure is disordered (Fig. 2D-5). There is much higher electron density in nuclear and cytoplasmic substances (Fig. 2B-b, C-b and E-b).

Activities of ALP, ACP, SDH and ATPase in the ovary The activities of ALP, ACP and SDH in LG (P b 0.05), MG (P b 0.01) and HG (P b 0.01) were lower than those in CG (Fig. 4). The activities of Mg2+-ATPase, Na+–K+-ATPase and Ca2+-ATPase were lower in LG (P b 0.05), MG (P b 0.01) and HG (P b 0.01) than those in CG (Fig. 5).

Contents of Fe, Zn and Cu in the ovary Expressions of FSHR and LHR in the ovary The contents of Zn and Fe were decreased and the content of Cu was increased, in a dose-dependent manner, in the ovaries of rats treated with AlCl3. The contents of Zn and Fe in MG (P b 0.05) and HG (P b 0.01) were lower and the contents of Cu in MG (P b 0.05) and HG (P b 0.01) were higher than those in CG (Fig. 3).

The average gray scale was negatively correlated with the expression of FSHR/LHR protein. The increased gray scales of FSHR and LHR mean decreased expressions of FSHR and LHR. The active gray scales of FSHR in all Al-treated groups were higher (P b 0.05; P b 0.01) than


1 1 2

a b






4 2

3 5 2



Fig. 2. Electron microscopy image: ovarian tissue of rats in HG respectively at ×2500 (B), ×8200 (C), ×16,500 (D), and ×20,500 (E). 1: nuclear chromatin; 2: mitochondria; 3: rough endoplasmic reticulum; 4: nuclear envelope; 5: Golgi body; a: apoptosis ovary granulosa cells; b: high electron density substance.


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Fig. 4. The activity of ALP, ACP and SDH in ovaries of rats administrated with AlCl3 in drinking water for 120 days. CG control group, LG low-dose group, MG mid-dose group, HG high-dose group.*P b 0.05, **P b 0.01 versus control group.

those in CG. The active gray scales of LHR in MG and HG were higher (P b 0.01) than those in CG (Fig. 6). Discussion Our results indicate that AlCl3 disrupted the structure of the ovary and their functions, which may lead to infertility of female rats. AlCl3 was chosen because it is a form of highly enriched salt in the earth. Consumptions of AlCl3 damaged the structure of the ovary, disturbed the metabolic balances of trace minerals like Fe, Cu and Zn, inhibited the activities of many enzymes such as ACP, ALP, SDH, ATPase, and decreased the contents of LH and FSH (Wang et al., 2011) as well as the expressions of their receptors. These results imply that AlCl3 exposure disrupts the structure and function of the ovary, in general, by decreasing energy production and possible ovulation. The administration of AlCl3 damaged cell nucleus, mitochondria, rough endoplasmic reticulum and Golgi apparatus of the ovary granulosa cells, which possibly leads to suppressed ATP supply, secretion and activity of the enzyme, and then inhibits luteal function, oocyte maturation and embryo development (Fig. 2). Our study found that AlCl3 exposure caused the changes of the profiles of Zn, Fe and Cu in the ovary (Fig. 3). Zn, Fe and Cu affect the activities of ALP, SDH, ACP, FSH, LH (Hurley and Doane, 1989; Gambling et al., 2011; Hawk et al., 1998), and these enzymes are involved in the oxidative metabolism and the hormones in the ovulation

Fig. 5. The activities of Mg2+-ATPase, Na+–K+-ATPase and Ca2+-ATPase in ovary administrated with AlCl3 in drinking water for 120 days. CG control group, LG low-dose group, MG mid-dose group, HG high-dose group. *P b 0.05, **P b 0.01 versus control group.

Fig. 6. The expressions of FSHR and LHR in ovary of rats administrated with AlCl3 in drinking water for 120 days. CG control group, LG low-dose group, MG mid-dose group, HG high-dose group. *P b 0.05, **P b 0.01 versus control group.

and luteinization functions of the ovary. Fe can execute the combustion of citric acid and is heavily reliant of oxidative metabolism (Hentze et al., 2004). An overload of Al can disturb absorption of Fe by competitively combining with transferrin (TRF) which carries Fe from gastrointestinal absorption and released by a breakdown red cells (Bondy et al., 1998). In our study, the decreased Fe content in the ovary may be attributed to reduced absorption in the intestines. In addition, we found that Al decreased Zn content and increased Cu content (Fig. 3). Zn is a cofactor of lactate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase and malate dehydrogenase, and involved with energy metabolism and redox processes. Cu is the cofactor of cytochrome oxidase which is involved in the respiratory chain of hydrogen or electron transfer reactions. The disordered metabolisms of Cu and Zn inhibit the enzyme activity and oxidative phosphorylation, which can decrease the production of ATP. In contrast to our observations, Gómez et al. (2008) found that Al decreased Cu and increased Zn in the blood plasma of mice. Sun et al. (2011) reported that the Zn content in the testicular tissue of rats was significantly lowered by Al exposure. However, Al has no effect on the metabolism of Cu (Greger and Sutherland, 1997). The increased Cu content in the ovary found in this study may be attributed to liver damage which reduced metabolic ability of Cu in the liver and caused retention of Cu in the rat exposed to Al (Zhao, 2011). In addition, antagonism in metabolisms between Zn and Cu may explain their inverse relationship (Bremner and Beattie, 1995). When salts of Al enter cells, then they may directly bind to DNA and RNA helices, which prevent their replications and then inhibit the activities of ALP and ACP in organelles (Ochmanski and Barabasz, 2000). Al decreased the activities of ACP, ALP and SDH in the liver of rats (Fatm, 2004), but increases in the activity of ACP in the liver and kidney of rats were reported by Nikolova et al. (1994). Our study found that the activities of ACP, ALP and SDH all decreased with the increases of AlCl3 dosages (Fig. 4). The ALP activity reflects the growth of the follicle and lowered ALP activity could be related to reduced glucose metabolism and reduced energy supply in the ovary, and then it suppresses ovarian endocrine and oocyte maturation (Handerson and Cupps, 1990). ACP plays an important role in ovulation. The decreased activity of ACP inhibits ovulation and activity of phosphatase, so that ACP activity relates to the growth and atresia of the ovary (Handerson and Cupps, 1990). The decreased activities of ALP and SDH suppress the function of the ovary cells, even lead to death of the cell, and then inhibit the differentiation and development of the ovary (Rahman et al., 2000). SDH plays a key role in the mitochondrial metabolism both as a member of the electron transport chain and tricarboxylic acid cycle (TCA) (Araújo et al., 2011). The decreased SDH dampens mitochondrial electron transportation and oxidative respiration, and then hinders the TCA and the energy metabolism in the ovary cells of rats. It is well known that oocytes and

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embryos at the pre-compaction ‘cleavage’ stages of pre-implantation development derive ATP from the TCA (Leese, 1991, 1995, 2003). In summary, Al decreased the activities of ACP, ALP and SDH, possibly leading to suppressed ATP supply, luteal function, oocyte maturation and embryo development. Na+–K+-ATPase, Mg2+-ATPase, and Ca2+-ATPase are the Na+, K+, Mg2+, Ca2+ ion pumps in cells, control the intracellular and extracellular movements of the ions to maintain transmembrane ion gradients (Speit and Merk, 2002). ATPase decomposes adenosine triphosphate (ATP) and releases energy which is used for the membrane transport of various ions. For example, each cycle of the Na+–K+-ATPase activity extrudes 3 Na+ from the cell and moves 2 K+ into the cell with utilization of 1 ATP. Hence, decreased activity of ATPase in this study could suppress transductive process of energy and disturb the ion balances (Fig. 5). Sushma and Rao (2007) found that total ATPase activity was significantly reduced in multiple tissues of rats under Al acetate intoxication. Bimla et al. (2006) found a significantly decreased activity of Mg 2 +-ATPase in the cerebrum and cerebellum of rats exposed to Al. Silva et al. (2005) observed that chronic dietary AlCl3 administration decreased brain Na+/K+-ATPase activity, intracellular energy production, and incomplete cell membrane. The decreased activities of Mg2 +-ATPase, Na+–K+-ATPase and Ca2 +-ATPase cause Mg2 + deficiency and Na+, Ca2 + overload in cells and then decrease activities of intracellular enzymes involved in energy metabolism. In addition, intracellularly overloaded Ca2+ causes a mitochondrial damage, metabolic disturbance of energy and decreases generation of ATP (Bartolommei et al., 2008). The subunit parts of Na+–K+-ATPase and Ca2+-ATPase locate the outer layer of the cell membrane, and Al can bind to their functional positions, then disorder the ion flow and suppress energy supply (Meiri et al., 1993). Al has a greater binding capacity with ATP compared with Mg, so Al binds to ATP, forming an Al–ATP complex, and thereby, competitively inhibits the activity of Mg2 +ATPase (Sylvia and Gareth, 1993). In summary, Al competitively binds to the functional sites or competes with the co-factor ions Mg2 +ATPase, Na+–K+-ATPase and Ca2 +-ATPase which are responsible for ion transport across cell membranes, and cause disordered transport, leading to suppressed energy metabolism and imbalanced osmolality, and then cell swelling and apoptosis. Our previous studies showed that AlCl3 exposure inhibited secretion of FSH and LH (Wang et al., 2011; Ige and Akhigbe, 2012). In this study, AlCl3 exposure decreased the density of FSHR and LHR, and weaken FSH–FSHR, and LH–LHR combinations (Fig. 6). FSH and LH are synthesized in the pituitary gland and are important for stimulating oocyte maturation in mammals (Kumar et al., 1997). The number and activity of the ovary follicles are associated with FSH and LH levels. FSH and LH, as major components of the hypothalamic–pituitary–gonad axis, regulate reproductive function and ultimately the production of gametes and fertility. The physiological functions of FSH and LH are mediated by specific receptors—FSHR and LHR (Thomas et al., 2007). The FSHR and LHR density and structure can directly affect the function of FSH and LH. FSH must bind to FSHR located on the granulosa cell membrane (Allen et al., 2003; Ranniki et al., 1995) to service its roles. The interaction between FSH and FSHR is essential for the oogenesis. After the FSHR gene is knocked in mice, the shrinkage of the ovary occurs and follicle development stops (Abel et al., 2000). LH promotes follicular maturation (Campbell et al., 1995), ovulation (Hunter et al., 2004), and corpus luteum development (Niswender et al., 2000), and relates with the synthesis of FSH as well as the ovary regulation (Rao, 2001). Decreased LH could reduce ovulation and FSH secretion, and result in irregular development of the ovary follicles, such as follicular atresia, degeneration, and bubble-shaped cavity (Trif et al., 2010). The density of LHR in the ovary is closely connected with follicular development and ovulation. Therefore, we deduced that AlCl3 decreased the density of FSHR and LHR, and weakened FSH–FSHR, and LH–LHR combinations which lead to suppressed ovulation and corpus luteum development, and then caused follicular atresia and degeneration.


In conclusion, the sub-chronic AlCl3 exposure damaged the structure and function of the ovary, decreased the contents of Zn, Fe, Cu and the activities of ACP, ALP, SDH and ATPase in the ovary and resulted in suppressed ATP supply, luteal function, oocyte maturation and embryo development in this study. In addition, AlCl3 decreased the density of FSHR and LHR, and weakened FSH–FSHR, and LH–LHR combinations, leading to damage of the reproductive function. It is appealing that the detrimental effects of AlCl3 are mediated through imbalance of the trace minerals on energy supply in the ovary, as well as on the reproductive hormones. AlCl3 may have other mechanisms on the ovary damage, such as the signaling pathways towards female infertility, which is worthy of further studies. Conflict of interest statement There are no conflicts of interests.

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Effects of sub-chronic aluminum chloride exposure on rat ovaries.

This experiment investigated the effects of sub-chronic aluminum chloride (AlCl3) exposure on rat ovaries...
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