Article
Effects of aluminum chloride on the serum protein, bilirubin and hepatic trace elements in chickens
Toxicology and Industrial Health 1–7 © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0748233715578035 tih.sagepub.com
Ben Wang1, Yanzhu Zhu2, Hongling Zhang1, Liming Liu1, Guojiang Li1, Yongli Song1 and Yanfei Li3 Abstract The aim of this study was to reveal the effects of aluminum chloride (AlCl3) on the hepatic metabolism function and trace elements’ distribution. Two hundred healthy male chickens (1 day old) were intraperitoneally administered with AlCl3 (0, 18.31, 27.47, and 36.62 mg kg1 day1 of Al3þ) consecutively for 3 days. Then the chickens were allowed to rest for 1 day. The cycle lasted four days. The cycle was repeated 15 times (60 days). The contents of serum total protein (TP), albumin (ALB), total bilirubin (TBI), direct bilirubin (DBI), hepatic aluminum (Al), copper (Cu), iron (Fe), and zinc (Zn) were examined. The results showed that the contents of serum TP and ALB and hepatic Fe and Zn decreased and the contents of serum TBI and DBI and hepatic Al and Cu increased in the chickens with AlCl3. This indicates that chronic administration of AlCl3 impairs the hepatic metabolism function and disorders the hepatic trace elements’ distribution. Keywords Al, liver, chickens, trace elements, protein, bilirubin
Introduction Aluminum (Al) is ubiquitous in the environment, so Al exposure is inevitable to increase a potential risk for humans and animals (Hewitt and Savory, 1990; Rengel, 2004). Livers from male Wistar rats were perfused in a recirculating system for 240 min, and at higher Al levels of 6535.3–16694.9 g l1 signs of toxicity toward isolated perfused livers were observed as indicated by an increased release of the enzymes aspartate aminotransferase and alanine transaminase into the perfusate, a pronounced reduction of bile flow rate and a 50% suppression of oxygen consumption (Wilhelm et al., 1996). Moreover, a systems biology approach in cultured hepatoblastoma cells (HepG2) was used to identify the molecular targets of Al toxicity and found that mitochondrial metabolism is the main site of the toxicological action of Al. Additionally, Al toxicity leads to an increase in intracellular lipid accumulation due to enhanced lipogenesis and a decrease in the -oxidation of fatty acids (Mailloux et al., 2011). Later Alemmari et al. (2011) found marked blunting of bile canaliculi microvilli in the pigs with aluminum chloride (AlCl3), serum total bile acids and hepatic Al concentration correlated with the
duration of Al exposure. Though the hepatic Al toxicity was observed, effects of Al on the hepatic metabolism function and trace elements’ distribution remain elusive. Total protein (TP) and albumin (ALB) were important indexes to response hepatic protein synthesis. Liver produces 90% of the proteins in an organism. TP and ALB were the dominant components of the proteins. Serum TP and ALB contents significantly decreased in rats that were orally administrated with AlCl3 (8.5 mg kg1 body weight (B.W.) for 8 weeks) (Fyiad, 2007). Al induced the reduction of TP and ALB, but Al dose was low. Serum ALB content was
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College of Veterinary Medicine, Jilin Science and Technology Vocational College, Jilin, China 2 Institute of Special Animal and Plant Sciences of Chinese Academy of Agricultural Sciences, Changchun, China 3 College of Veterinary Medicine, Northeast Agricultural University, Harbin, China Corresponding author: Yanfei Li, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China. Email: [email protected]
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decreased in rats that were administered with Al (32.5 mg kg1, 24 h) (Bhadauria, 2012). It revealed that Al induced the reduction of ALB without TP, and exposure time was short. Total bilirubin (TBI) and direct bilirubin (DBI) can reflect the injury of hepatic secretion and excretory function. The TBI released from senile erythrocytes transferred to the surface of hepatocytes by blood circulation. DBI was formed by the combination between TBI and glucuronic acid. Gao et al. (2007) found that serum TBI content decreased in the rats with AlCl3 by gavage. A significant increase of TBI and cholesterol was observed in rats that were orally administrated with AlCl3 (8.5 mg kg1 B.W. for 8 weeks) (Fyiad, 2007). In addition, TBI and DBI contents were significantly increased in the workers who were exposed to 4.6 mg m3 of Al dust and fumes in workplace air for 21.6 + 2.5 years (Bogdanovic´ and Bulat, 2008). The workers were present in complex conditions, and thus other factors might affect the results. Iron (Fe), zinc (Zn), and copper (Cu) are essential trace elements for the hepatic function. Fe regulates glucose homeostasis via AMP-activated protein kinase in liver of mice (Huang et al., 2013). Cu facilitates the formation of reactive oxygen species that can damage DNA and chromatin (Linder, 2012). Zn is essential for the activity of enzymes and transcription factors, and Zn deficiency was present in patients with liver disease (Prasad, 2013). In pregnant rats, the hepatic concentrations of Fe, Zn, and Cu were significantly higher in the Al-treated rats compared with the control (Belle´s et al., 2001). It focused on the hepatic distribution of Fe, Zn, and Cu with Al exposure, but the rats were pregnant and the data were recorded under complex conditions. Therefore, effects of Al (as AlCl3, measured as Al) on the serum protein (measured as TP and ALB), serum bilirubin (measured as TBI and DBI), and hepatic trace elements (measured as Fe, Zn, and Cu) were examined to find the effects of AlCl3 on the hepatic metabolism function and trace elements’ distribution.
Materials and methods Chickens The chickens were acclimatized for 1 week. Two hundred healthy male chickens (1 day old) were randomly allocated equally into control group (CG, 0), low-dose group (LG, 18.31 mg kg1 day1 of Al3þ), mid-dose
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group (MG, 27.47 mg kg1 day1 of Al3þ), and highdose group (HG, 36.62 mg kg1 day1 of Al3þ). Each group had 50 chickens. Throughout the experiment, chickens were intraperitoneally administered with AlCl3 consecutively for 3 days. Then the chickens were injected with 2500 IU of penicillin and streptomycin when the chickens were allowed to rest for 1 day. Four days was a cycle. The cycle was repeated 15 times (60 days). The chickens were given drinking water and food addiction ad libitum. Chickens were housed in the Biomedical Research Center, Jilin Science and Technology Vocational College, China. The housing conditions were maintained at a temperature of 24 + 1 C and a 12-h light/12-h dark cycle. The chickens were kept in plastic cages (five chickens per cage) with soft chip bedding. The size of all the cages was 600 625 280 mm3, large enough for the growth of five chickens. The health status of chickens was observed daily and body weight of the chickens was recorded every week.
Sample collection The experimental protocol was approved by the Ethics Committee on the Use and Care of Animals, Jilin Science and Technology Vocational College, China. After 60 days, the chickens were anesthetized with ether and were killed. Then the blood samples and livers were collected from each chicken. The blood sample was used to obtain serum to determine the contents of TP, ALB, TBI, and DBI. The liver was used to examine the contents of Al, Fe, Zn, and Cu.
The detection of TP, ALB, TBI, and DBI in the serum The serum concentrations of TP, ALB, TBI, and DBI were measured according to the study by Oyagbemi et al. (2013).
The detection of Al, Fe, Zn, and Cu in the liver The contents of hepatic Al were determined using a graphite furnace atomic absorption spectrophotometer, and the contents of hepatic Fe, Zn, and Cu were determined using a flame atomic absorption spectrophotometer according to Zhu et al. (2012).
Statistical analysis Statistical analyses were done using SPSS 15.0 package programmer (SPSS Inc., Chicago, Illinois, USA). One-way analysis of variance followed by Student’s
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678.3. 673.1 669.5 667.1 0.073 0.463b 0.064b 0105b 552.2 + 546.8 + 547.5 + 544.2 + 0.033 0.583a 0.024b 0.063b + + + + 454.8 451.6 447.5 448.6 + 0.063 + 0.153a + 0.085b + 0.253b 366.9 363.2 358.6 358.1 + 0.053 + 0.113a + 0.303a + 0.635b 275.6 273.9 273.2 268.5 + 0.033 + 0.263b + 0.013b + 0.063b 195.8 187.5 185.6 186.5 + 0.133 + 0.113a + 0.563b + 0.033b 125.4 123.2 123.8 119.7
CG: control group; LG: low-dose group; MG: mid-dose group; HG: high-dose group. a p < 0.05 versus CG. b p < 0.01 versus CG.
Al pollutants are a global health risk due to their ability to cause a variety of diseases. Al accumulates in
+ + + +
Discussion
CG LG MG HG
Contents of hepatic Al and Cu in chickens increased with AlCl3. The contents of Al in LG, MG, and HG were significantly higher than those in CG (p < 0.01). Cu contents in MG and HG were higher than those in CG (p < 0.05). Contents of hepatic Fe and Zn in chickens decreased with AlCl3. Fe contents in MG and HG were lower than those in CG (p < 0.05). Zn contents in MG (p < 0.05) and HG (p < 0.01) were lower than those in CG (Table 4).
21-Day old (g)
Effects of Al on hepatic Al, Fe, Zn, and Cu contents
14-Day old (g)
Contents of TBI and DBI in the serum of chickens increased with AlCl3. The contents of TBI in MG and HG were higher than those in CG (p < 0.01). The contents of DBI in MG (p < 0.05) and HG (p < 0.01) were higher than those in CG (Table 3).
7-Day old (g)
Effects of Al on serum TBI and DBI contents
Table 1. The body weight of chicken (means + SD, n ¼ 50 per group).
Contents of TP and ALB in the serum of chickens decreased with AlCl3. The contents of TP in MG (p < 0.05) and HG (p < 0.01) were lower than those in CG. The contents of ALB in LG (p < 0.05), MG (p < 0.01), and HG (p < 0.01) were lower than those in CG (Table 2).
Item
Effects of Al on serum TP and ALB contents
28-Day old (g)
35-Day old (g)
42-Day old (g)
No chicken died during the experiment. The chickens with AlCl3 were less active than those in the control. The body weight of chickens in four groups increased continuously throughout the experimental period, and the body weight of AlCl3-treated chickens was significantly lower than that of CG (p < 0.05 and p < 0.01; Table 1).
75.6 74.2 75.1 76.2
Results Effects of Al on the body weight
0.011 0.033a 0.046 0.061a
49-Day old (g)
56-Day old (g)
t-test was used to compare the effects of different contents of AlCl3 exposure on the serum protein, bilirubin, and hepatic trace elements with CG. Data were shown as means and standard deviation. A p value of less than 0.05 was considered significant and a p value of less than 0.01 was considered markedly significant.
+ 0.153 + 0.052b + 0.523b + 0.634b
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Table 2. Effects of Al on the TP and ALB in serum of chicken (means + SD, n ¼ 50 per group). Item CG LG MG HG
TP (g l1) 53.26 + 51.38 + 49.62 + 45.76 +
7.23 5.64 3.45a 4.98b
ALB (g l1) 15.12 13.23 11.54 10.58
+ 3.90 + 2.98a + 1.96b + 2.56b
CG: control group; LG: low-dose group; MG: mid-dose group: HG: high-dose group; TP: total protein; ALB: albumin; Al: aluminum. a p < 0.05 versus CG. b p < 0.01 versus CG.
Table 3. Effects of Al on the TBI and DBI in serum of chicken (means + SD, n ¼ 50 per group). Item
TBI (mol l1)
CG LG MG HG
7.10 + 8.43 + 10.13 + 11.36 +
0.75 090 2.23a 3.42a
DBI (mol l1) 6.25 + 7.77 + 8.20 + 9.00 +
0.89 1.02 0.56b 0.85a
CG: control group; LG: low-dose group; MG: mid-dose group; HG: high-dose group; TBI: total bilirubin; DBI: direct bilirubin; Al: aluminum. a p < 0.01 versus CG. b p < 0.05 versus CG.
the liver (Willhite et al., 2012), and liver participates in the metabolic function of an organism. The accumulation of hepatic Al would impair the metabolic function of the liver. This experiment focused on the effects of Al on the hepatic metabolism function and trace elements’ distribution. The contents of TP and ALB response the metabolism function of the liver. In the present experiment, AlCl3 decreased the contents of TP and ALB in the serum of chickens. The transportation, synthesis, and disintegration of protein were related to the function of liver. Al impaired the hepatic structure and that caused the reduction of TP and ALB in the serum of chickens. Mosoni et al. (1996) found that motion promoted protein synthesis. In the present experiment, the chickens with AlCl3 were less active. It might result in the reduction of TP and ALB in the serum of chickens. Oxidative stress was observed in the liver of rats with Al exposure (Chaitanya et al., 2012). Oxidative stress impaired proper protein synthesis (Ling and So¨ll, 2010). Thus, the hepatic oxidative stress induced by Al pollutants caused the reduction of TP and ALB. Zn regulated the synthesis of specific proteins in the liver of rats through the changes of the relative abundance of specific messenger RNA
(Kimball et al., 1995). In the present experiment, hepatic Zn content decreased in the chickens with AlCl3. Thus, the reduction of hepatic Zn content might reduce the contents of TP and ALB. The reduction of TP in the present experiment indicated that Al impaired the hepatic protein synthesis in the chickens. ALB could combine many toxins and attenuate the toxic effects of toxins. The decrease of ALB weakened the hepatic Al detoxification and indirectly enhanced the toxicity of Al. Gao et al. (2007) confirmed that serum TP content decreased when rats were exposed to AlCl3 through gavage for 3 weeks. After the usage of 1,2-dimethyl-3-hydroxy4-pyridone, hepatic Al concentration was significantly decreased and protein synthesis was recovered. It indicates that Al exerts the toxic effect by suppressing the hepatic protein metabolism. Bilirubin is produced when the senile erythrocytes are decomposited and destructed in liver, spleen, and bone marrow mononuclear phagocyte system. The high level of bilirubin is related to the disorder of hepatocytes, abnormal hemolysis, and biliary obstruction disease. In the present experiment, serum TBI and DBI contents increased in the chickens with AlCl3. The metabolism of TBI and DBI was mediated by the hepatocytes. The TBI and DBI contents would be increased when hepatocytes do not metabolize TBI and DBI completely. The blocked excretion of TBI and DBI would also result in the increase of serum TBI and DBI. Sinusoidal dilatation, congestion of central vein, lipid accumulation, and lymphocyte infiltration were observed in liver when the rats were orally administrated with 34 mg AlCl3 kg1 B.W. daily for 30 days (Tu¨rkez et al., 2010). The hepatic pathohistological change affected the function of hepatocytes. Thus, the increases of TBI and DBI contents were induced by hepatic pathohistological change through impaired hepatocytes. Al decreased the number of erythrocytes and induced anemia in the rats (Zhang et al., 2011). Hemoglobin was released from the damage of erythrocytes. Most TBI derived from hemoglobin of the splitting erythrocytes. TBI and DBI were the ultimate breakdown products of hemoglobin. This would result in the increase of serum TBI and DBI contents. Bilirubin is tightly bound to circulating ALB (Wang et al., 2006). In the present experiment, serum TBI and DBI contents increased and serum ALB contents decreased in chickens with AlCl3. It might be that the reduction of ALB content was not enough to conjugate all the bilirubin in serum and induced the
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Table 4. The contents of Al, Fe, Zn, and Cu in the liver of the chicken (means + SD, n ¼ 50 per group). Item CG LG MG HG
Al 7.559 16.534 65.129 69.307
+ 2.548 + 4.619a + 5.238a + 7.193a
Fe 154.676 + 127.051 + 93.566 + 69.166 +
Zn 16.519 31.937 9.545b 6.607b
43.667 41.067 36.935 34.985
+ 2.167 + 1.379 + 1.313b + 1.182a
Cu 4.831 + 6.674 + 7.221 + 7.821 +
1.449 0.510 0.336b 0.736b
CG: control group; LG: low-dose group; MG: mid-dose group; HG: high-dose group; Al: aluminum; Cu: copper; Fe: iron; Zn: zinc. a p < 0.01 versus CG. b p < 0.05 versus CG.
increase of TBI and DBI contents. The increased TBI and DBI contents would penetrate cell membrane and induce toxicity. Increase of bilirubin concentration caused serious nerve injury (Miao et al., 2010). The excessive bilirubin combined with the lipid in the nuclei basales of brain, which impaired the brain function. It indicates that Al exerts neurotoxicity by suppressing hepatic bilirubin metabolism. Bilirubin is an important pigment in the bile. Bile is an important route of Al excretion in male SpragueDawley rats (Sutherland et al., 1996). Serum total bile acid contents were increased and marked blunting of bile canaliculi microvilli was observed in domestic pigs that were intravenously administered with AlCl3 at 1500 g kg1 day1 for 1, 2, 3, or 4 weeks (Alemmari et al., 2012). The subclinical sign of cholestasis was manifested in the workers with impaired biliary secretion (Bogdanovic´ and Bulat, 2008). It indicates that AlCl3 induces the increase of TBI and DBI in the serum by blocking the bile acid excretion. Fe, Zn, and Cu are essential trace elements for protein synthesis and production of enzymes. In the present experiment, hepatic Fe content was decreased in the chickens with AlCl3. Fe was present in the liver with ferritin (Munro and Linder, 1978). Transferritin was mainly from hepatocytes (Mason and Taylor, 1978). Liver maintained the Fe homeostasis by regulation of the transferritin and transferritin receptor (Takami and Sakaida, 2011). Al impaired the hepatic structure and it might disorder Fe homeostasis and reduce Fe content. Moreover, the absorption of Fe and Al were mainly carried by transferritin, and Al competed with Fe in ferritin and transferritin (Cochran et al., 1984). Van Landeghem et al. (1994) confirmed that Al would compete with Fe for the Fe-binding protein. The decrease of hepatic Fe content in the present study may attribute to the competition of Al with Fe. Fe deficiency would decrease the activity of enzymes and disorder the metabolism of organism
(Boldt, 1999). The absence of Fe would block the metabolism of protein and induce abnormal function of the liver. Fe was an important component of catalase. The absence of Fe would result in the lower activity of catalase and inhibit the antioxidant ability. It showed that oxidative stress was observed in the liver with Al exposure (Chaitanya et al., 2012). So the hepatic oxidative stress might attribute to the Fe deficiency induced by AlCl3. Mammalian Fe absorption was primarily controlled by the hepatocyte-derived peptide hepcidin, encoded by the HAMP gene. Hepcidin regulated ferroportinmediated Fe export from enterocytes and macrophages, thus determined dietary Fe uptake as well as the amount of Fe available for erythropoiesis (Krijt et al., 2012). Al might injure the hepcidin and decrease Fe content in the liver. In our previous research, microsomal protein and nicotinamide adenine dinucleotide phosphate-cytochrome c reductase decreased in the rats with AlCl3 (Zhu et al., 2013). It indicates that Al exerts hepatic toxicity by the induction of apoptosis. In the present experiment, hepatic Zn content decreased and hepatic Cu content increased in the chickens with AlCl3. Zn and Cu had antagonism relationship. The increase of Cu might attribute to the decrease of Zn. Cu facilitated the formation of reactive oxygen species that damaged DNA and chromatin (Linder, 2012). The overload of Cu would induce lipid peroxidation in the mitochondria of hepatocytes (Sokol et al., 1990). Zn was also an antioxidant and anti-inflammatory agent (Linder, 2012). Zn deficiency would induce oxidative injury and impair the membrane of hepatocytes. The oxidative stress in liver induced by Al was observed (Viezeliene et al., 2011). It indicates that Al affects hepatic Cu and Zn contents and induces oxidative stress in the liver. The latest evidence showed that Al might mediate Alzheimer’s disease through liver toxicity and the excess free Cu caused brain oxidation and -amyloid aggregation
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(Brenner, 2013). Zn was effective in attenuating the liver damage inflicted by Al toxicity (Bhasin et al., 2014). The reduction of Zn will decrease the function of hepatic detoxification. It suggests that AlCl3 induces oxidative stress by the reduction of Zn and the increase of Cu. In conclusion, the decreases of serum TP and ALB and hepatic Fe and Zn contents and the increases of serum TBI and DBI and hepatic Al and Cu contents indicate that the chronic administration of AlCl3 induces cumulative effect, damages hepatic metabolism function and disorders trace element distribution. Authors’ Note Ben Wang and Yanzhu Zhu contributed equally to this study. Jilin Science and Technology Vocational College and Institute of Special Animal and Plant Sciences of Chinese Academy of Agricultural Sciences, Changchun 130112, China, contributed equally to this study.
Funding The study was supported by a Grant from the National Science Foundation Project (31172375, 31302147), the Youth Station in Jilin Science and Technology Vocational College (01002) and Science Foundation for Young Scientists of Jilin Province (20130522091JH).
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Effects of aluminum chloride on the serum protein, bilirubin and hepatic trace elements in chickens
Toxicology and Industrial Health 1–7 © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0748233715578035 tih.sagepub.com
Ben Wang1, Yanzhu Zhu2, Hongling Zhang1, Liming Liu1, Guojiang Li1, Yongli Song1 and Yanfei Li3 Abstract The aim of this study was to reveal the effects of aluminum chloride (AlCl3) on the hepatic metabolism function and trace elements’ distribution. Two hundred healthy male chickens (1 day old) were intraperitoneally administered with AlCl3 (0, 18.31, 27.47, and 36.62 mg kg1 day1 of Al3þ) consecutively for 3 days. Then the chickens were allowed to rest for 1 day. The cycle lasted four days. The cycle was repeated 15 times (60 days). The contents of serum total protein (TP), albumin (ALB), total bilirubin (TBI), direct bilirubin (DBI), hepatic aluminum (Al), copper (Cu), iron (Fe), and zinc (Zn) were examined. The results showed that the contents of serum TP and ALB and hepatic Fe and Zn decreased and the contents of serum TBI and DBI and hepatic Al and Cu increased in the chickens with AlCl3. This indicates that chronic administration of AlCl3 impairs the hepatic metabolism function and disorders the hepatic trace elements’ distribution. Keywords Al, liver, chickens, trace elements, protein, bilirubin
Introduction Aluminum (Al) is ubiquitous in the environment, so Al exposure is inevitable to increase a potential risk for humans and animals (Hewitt and Savory, 1990; Rengel, 2004). Livers from male Wistar rats were perfused in a recirculating system for 240 min, and at higher Al levels of 6535.3–16694.9 g l1 signs of toxicity toward isolated perfused livers were observed as indicated by an increased release of the enzymes aspartate aminotransferase and alanine transaminase into the perfusate, a pronounced reduction of bile flow rate and a 50% suppression of oxygen consumption (Wilhelm et al., 1996). Moreover, a systems biology approach in cultured hepatoblastoma cells (HepG2) was used to identify the molecular targets of Al toxicity and found that mitochondrial metabolism is the main site of the toxicological action of Al. Additionally, Al toxicity leads to an increase in intracellular lipid accumulation due to enhanced lipogenesis and a decrease in the -oxidation of fatty acids (Mailloux et al., 2011). Later Alemmari et al. (2011) found marked blunting of bile canaliculi microvilli in the pigs with aluminum chloride (AlCl3), serum total bile acids and hepatic Al concentration correlated with the
duration of Al exposure. Though the hepatic Al toxicity was observed, effects of Al on the hepatic metabolism function and trace elements’ distribution remain elusive. Total protein (TP) and albumin (ALB) were important indexes to response hepatic protein synthesis. Liver produces 90% of the proteins in an organism. TP and ALB were the dominant components of the proteins. Serum TP and ALB contents significantly decreased in rats that were orally administrated with AlCl3 (8.5 mg kg1 body weight (B.W.) for 8 weeks) (Fyiad, 2007). Al induced the reduction of TP and ALB, but Al dose was low. Serum ALB content was
1
College of Veterinary Medicine, Jilin Science and Technology Vocational College, Jilin, China 2 Institute of Special Animal and Plant Sciences of Chinese Academy of Agricultural Sciences, Changchun, China 3 College of Veterinary Medicine, Northeast Agricultural University, Harbin, China Corresponding author: Yanfei Li, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China. Email: [email protected]
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decreased in rats that were administered with Al (32.5 mg kg1, 24 h) (Bhadauria, 2012). It revealed that Al induced the reduction of ALB without TP, and exposure time was short. Total bilirubin (TBI) and direct bilirubin (DBI) can reflect the injury of hepatic secretion and excretory function. The TBI released from senile erythrocytes transferred to the surface of hepatocytes by blood circulation. DBI was formed by the combination between TBI and glucuronic acid. Gao et al. (2007) found that serum TBI content decreased in the rats with AlCl3 by gavage. A significant increase of TBI and cholesterol was observed in rats that were orally administrated with AlCl3 (8.5 mg kg1 B.W. for 8 weeks) (Fyiad, 2007). In addition, TBI and DBI contents were significantly increased in the workers who were exposed to 4.6 mg m3 of Al dust and fumes in workplace air for 21.6 + 2.5 years (Bogdanovic´ and Bulat, 2008). The workers were present in complex conditions, and thus other factors might affect the results. Iron (Fe), zinc (Zn), and copper (Cu) are essential trace elements for the hepatic function. Fe regulates glucose homeostasis via AMP-activated protein kinase in liver of mice (Huang et al., 2013). Cu facilitates the formation of reactive oxygen species that can damage DNA and chromatin (Linder, 2012). Zn is essential for the activity of enzymes and transcription factors, and Zn deficiency was present in patients with liver disease (Prasad, 2013). In pregnant rats, the hepatic concentrations of Fe, Zn, and Cu were significantly higher in the Al-treated rats compared with the control (Belle´s et al., 2001). It focused on the hepatic distribution of Fe, Zn, and Cu with Al exposure, but the rats were pregnant and the data were recorded under complex conditions. Therefore, effects of Al (as AlCl3, measured as Al) on the serum protein (measured as TP and ALB), serum bilirubin (measured as TBI and DBI), and hepatic trace elements (measured as Fe, Zn, and Cu) were examined to find the effects of AlCl3 on the hepatic metabolism function and trace elements’ distribution.
Materials and methods Chickens The chickens were acclimatized for 1 week. Two hundred healthy male chickens (1 day old) were randomly allocated equally into control group (CG, 0), low-dose group (LG, 18.31 mg kg1 day1 of Al3þ), mid-dose
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group (MG, 27.47 mg kg1 day1 of Al3þ), and highdose group (HG, 36.62 mg kg1 day1 of Al3þ). Each group had 50 chickens. Throughout the experiment, chickens were intraperitoneally administered with AlCl3 consecutively for 3 days. Then the chickens were injected with 2500 IU of penicillin and streptomycin when the chickens were allowed to rest for 1 day. Four days was a cycle. The cycle was repeated 15 times (60 days). The chickens were given drinking water and food addiction ad libitum. Chickens were housed in the Biomedical Research Center, Jilin Science and Technology Vocational College, China. The housing conditions were maintained at a temperature of 24 + 1 C and a 12-h light/12-h dark cycle. The chickens were kept in plastic cages (five chickens per cage) with soft chip bedding. The size of all the cages was 600 625 280 mm3, large enough for the growth of five chickens. The health status of chickens was observed daily and body weight of the chickens was recorded every week.
Sample collection The experimental protocol was approved by the Ethics Committee on the Use and Care of Animals, Jilin Science and Technology Vocational College, China. After 60 days, the chickens were anesthetized with ether and were killed. Then the blood samples and livers were collected from each chicken. The blood sample was used to obtain serum to determine the contents of TP, ALB, TBI, and DBI. The liver was used to examine the contents of Al, Fe, Zn, and Cu.
The detection of TP, ALB, TBI, and DBI in the serum The serum concentrations of TP, ALB, TBI, and DBI were measured according to the study by Oyagbemi et al. (2013).
The detection of Al, Fe, Zn, and Cu in the liver The contents of hepatic Al were determined using a graphite furnace atomic absorption spectrophotometer, and the contents of hepatic Fe, Zn, and Cu were determined using a flame atomic absorption spectrophotometer according to Zhu et al. (2012).
Statistical analysis Statistical analyses were done using SPSS 15.0 package programmer (SPSS Inc., Chicago, Illinois, USA). One-way analysis of variance followed by Student’s
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678.3. 673.1 669.5 667.1 0.073 0.463b 0.064b 0105b 552.2 + 546.8 + 547.5 + 544.2 + 0.033 0.583a 0.024b 0.063b + + + + 454.8 451.6 447.5 448.6 + 0.063 + 0.153a + 0.085b + 0.253b 366.9 363.2 358.6 358.1 + 0.053 + 0.113a + 0.303a + 0.635b 275.6 273.9 273.2 268.5 + 0.033 + 0.263b + 0.013b + 0.063b 195.8 187.5 185.6 186.5 + 0.133 + 0.113a + 0.563b + 0.033b 125.4 123.2 123.8 119.7
CG: control group; LG: low-dose group; MG: mid-dose group; HG: high-dose group. a p < 0.05 versus CG. b p < 0.01 versus CG.
Al pollutants are a global health risk due to their ability to cause a variety of diseases. Al accumulates in
+ + + +
Discussion
CG LG MG HG
Contents of hepatic Al and Cu in chickens increased with AlCl3. The contents of Al in LG, MG, and HG were significantly higher than those in CG (p < 0.01). Cu contents in MG and HG were higher than those in CG (p < 0.05). Contents of hepatic Fe and Zn in chickens decreased with AlCl3. Fe contents in MG and HG were lower than those in CG (p < 0.05). Zn contents in MG (p < 0.05) and HG (p < 0.01) were lower than those in CG (Table 4).
21-Day old (g)
Effects of Al on hepatic Al, Fe, Zn, and Cu contents
14-Day old (g)
Contents of TBI and DBI in the serum of chickens increased with AlCl3. The contents of TBI in MG and HG were higher than those in CG (p < 0.01). The contents of DBI in MG (p < 0.05) and HG (p < 0.01) were higher than those in CG (Table 3).
7-Day old (g)
Effects of Al on serum TBI and DBI contents
Table 1. The body weight of chicken (means + SD, n ¼ 50 per group).
Contents of TP and ALB in the serum of chickens decreased with AlCl3. The contents of TP in MG (p < 0.05) and HG (p < 0.01) were lower than those in CG. The contents of ALB in LG (p < 0.05), MG (p < 0.01), and HG (p < 0.01) were lower than those in CG (Table 2).
Item
Effects of Al on serum TP and ALB contents
28-Day old (g)
35-Day old (g)
42-Day old (g)
No chicken died during the experiment. The chickens with AlCl3 were less active than those in the control. The body weight of chickens in four groups increased continuously throughout the experimental period, and the body weight of AlCl3-treated chickens was significantly lower than that of CG (p < 0.05 and p < 0.01; Table 1).
75.6 74.2 75.1 76.2
Results Effects of Al on the body weight
0.011 0.033a 0.046 0.061a
49-Day old (g)
56-Day old (g)
t-test was used to compare the effects of different contents of AlCl3 exposure on the serum protein, bilirubin, and hepatic trace elements with CG. Data were shown as means and standard deviation. A p value of less than 0.05 was considered significant and a p value of less than 0.01 was considered markedly significant.
+ 0.153 + 0.052b + 0.523b + 0.634b
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Table 2. Effects of Al on the TP and ALB in serum of chicken (means + SD, n ¼ 50 per group). Item CG LG MG HG
TP (g l1) 53.26 + 51.38 + 49.62 + 45.76 +
7.23 5.64 3.45a 4.98b
ALB (g l1) 15.12 13.23 11.54 10.58
+ 3.90 + 2.98a + 1.96b + 2.56b
CG: control group; LG: low-dose group; MG: mid-dose group: HG: high-dose group; TP: total protein; ALB: albumin; Al: aluminum. a p < 0.05 versus CG. b p < 0.01 versus CG.
Table 3. Effects of Al on the TBI and DBI in serum of chicken (means + SD, n ¼ 50 per group). Item
TBI (mol l1)
CG LG MG HG
7.10 + 8.43 + 10.13 + 11.36 +
0.75 090 2.23a 3.42a
DBI (mol l1) 6.25 + 7.77 + 8.20 + 9.00 +
0.89 1.02 0.56b 0.85a
CG: control group; LG: low-dose group; MG: mid-dose group; HG: high-dose group; TBI: total bilirubin; DBI: direct bilirubin; Al: aluminum. a p < 0.01 versus CG. b p < 0.05 versus CG.
the liver (Willhite et al., 2012), and liver participates in the metabolic function of an organism. The accumulation of hepatic Al would impair the metabolic function of the liver. This experiment focused on the effects of Al on the hepatic metabolism function and trace elements’ distribution. The contents of TP and ALB response the metabolism function of the liver. In the present experiment, AlCl3 decreased the contents of TP and ALB in the serum of chickens. The transportation, synthesis, and disintegration of protein were related to the function of liver. Al impaired the hepatic structure and that caused the reduction of TP and ALB in the serum of chickens. Mosoni et al. (1996) found that motion promoted protein synthesis. In the present experiment, the chickens with AlCl3 were less active. It might result in the reduction of TP and ALB in the serum of chickens. Oxidative stress was observed in the liver of rats with Al exposure (Chaitanya et al., 2012). Oxidative stress impaired proper protein synthesis (Ling and So¨ll, 2010). Thus, the hepatic oxidative stress induced by Al pollutants caused the reduction of TP and ALB. Zn regulated the synthesis of specific proteins in the liver of rats through the changes of the relative abundance of specific messenger RNA
(Kimball et al., 1995). In the present experiment, hepatic Zn content decreased in the chickens with AlCl3. Thus, the reduction of hepatic Zn content might reduce the contents of TP and ALB. The reduction of TP in the present experiment indicated that Al impaired the hepatic protein synthesis in the chickens. ALB could combine many toxins and attenuate the toxic effects of toxins. The decrease of ALB weakened the hepatic Al detoxification and indirectly enhanced the toxicity of Al. Gao et al. (2007) confirmed that serum TP content decreased when rats were exposed to AlCl3 through gavage for 3 weeks. After the usage of 1,2-dimethyl-3-hydroxy4-pyridone, hepatic Al concentration was significantly decreased and protein synthesis was recovered. It indicates that Al exerts the toxic effect by suppressing the hepatic protein metabolism. Bilirubin is produced when the senile erythrocytes are decomposited and destructed in liver, spleen, and bone marrow mononuclear phagocyte system. The high level of bilirubin is related to the disorder of hepatocytes, abnormal hemolysis, and biliary obstruction disease. In the present experiment, serum TBI and DBI contents increased in the chickens with AlCl3. The metabolism of TBI and DBI was mediated by the hepatocytes. The TBI and DBI contents would be increased when hepatocytes do not metabolize TBI and DBI completely. The blocked excretion of TBI and DBI would also result in the increase of serum TBI and DBI. Sinusoidal dilatation, congestion of central vein, lipid accumulation, and lymphocyte infiltration were observed in liver when the rats were orally administrated with 34 mg AlCl3 kg1 B.W. daily for 30 days (Tu¨rkez et al., 2010). The hepatic pathohistological change affected the function of hepatocytes. Thus, the increases of TBI and DBI contents were induced by hepatic pathohistological change through impaired hepatocytes. Al decreased the number of erythrocytes and induced anemia in the rats (Zhang et al., 2011). Hemoglobin was released from the damage of erythrocytes. Most TBI derived from hemoglobin of the splitting erythrocytes. TBI and DBI were the ultimate breakdown products of hemoglobin. This would result in the increase of serum TBI and DBI contents. Bilirubin is tightly bound to circulating ALB (Wang et al., 2006). In the present experiment, serum TBI and DBI contents increased and serum ALB contents decreased in chickens with AlCl3. It might be that the reduction of ALB content was not enough to conjugate all the bilirubin in serum and induced the
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Table 4. The contents of Al, Fe, Zn, and Cu in the liver of the chicken (means + SD, n ¼ 50 per group). Item CG LG MG HG
Al 7.559 16.534 65.129 69.307
+ 2.548 + 4.619a + 5.238a + 7.193a
Fe 154.676 + 127.051 + 93.566 + 69.166 +
Zn 16.519 31.937 9.545b 6.607b
43.667 41.067 36.935 34.985
+ 2.167 + 1.379 + 1.313b + 1.182a
Cu 4.831 + 6.674 + 7.221 + 7.821 +
1.449 0.510 0.336b 0.736b
CG: control group; LG: low-dose group; MG: mid-dose group; HG: high-dose group; Al: aluminum; Cu: copper; Fe: iron; Zn: zinc. a p < 0.01 versus CG. b p < 0.05 versus CG.
increase of TBI and DBI contents. The increased TBI and DBI contents would penetrate cell membrane and induce toxicity. Increase of bilirubin concentration caused serious nerve injury (Miao et al., 2010). The excessive bilirubin combined with the lipid in the nuclei basales of brain, which impaired the brain function. It indicates that Al exerts neurotoxicity by suppressing hepatic bilirubin metabolism. Bilirubin is an important pigment in the bile. Bile is an important route of Al excretion in male SpragueDawley rats (Sutherland et al., 1996). Serum total bile acid contents were increased and marked blunting of bile canaliculi microvilli was observed in domestic pigs that were intravenously administered with AlCl3 at 1500 g kg1 day1 for 1, 2, 3, or 4 weeks (Alemmari et al., 2012). The subclinical sign of cholestasis was manifested in the workers with impaired biliary secretion (Bogdanovic´ and Bulat, 2008). It indicates that AlCl3 induces the increase of TBI and DBI in the serum by blocking the bile acid excretion. Fe, Zn, and Cu are essential trace elements for protein synthesis and production of enzymes. In the present experiment, hepatic Fe content was decreased in the chickens with AlCl3. Fe was present in the liver with ferritin (Munro and Linder, 1978). Transferritin was mainly from hepatocytes (Mason and Taylor, 1978). Liver maintained the Fe homeostasis by regulation of the transferritin and transferritin receptor (Takami and Sakaida, 2011). Al impaired the hepatic structure and it might disorder Fe homeostasis and reduce Fe content. Moreover, the absorption of Fe and Al were mainly carried by transferritin, and Al competed with Fe in ferritin and transferritin (Cochran et al., 1984). Van Landeghem et al. (1994) confirmed that Al would compete with Fe for the Fe-binding protein. The decrease of hepatic Fe content in the present study may attribute to the competition of Al with Fe. Fe deficiency would decrease the activity of enzymes and disorder the metabolism of organism
(Boldt, 1999). The absence of Fe would block the metabolism of protein and induce abnormal function of the liver. Fe was an important component of catalase. The absence of Fe would result in the lower activity of catalase and inhibit the antioxidant ability. It showed that oxidative stress was observed in the liver with Al exposure (Chaitanya et al., 2012). So the hepatic oxidative stress might attribute to the Fe deficiency induced by AlCl3. Mammalian Fe absorption was primarily controlled by the hepatocyte-derived peptide hepcidin, encoded by the HAMP gene. Hepcidin regulated ferroportinmediated Fe export from enterocytes and macrophages, thus determined dietary Fe uptake as well as the amount of Fe available for erythropoiesis (Krijt et al., 2012). Al might injure the hepcidin and decrease Fe content in the liver. In our previous research, microsomal protein and nicotinamide adenine dinucleotide phosphate-cytochrome c reductase decreased in the rats with AlCl3 (Zhu et al., 2013). It indicates that Al exerts hepatic toxicity by the induction of apoptosis. In the present experiment, hepatic Zn content decreased and hepatic Cu content increased in the chickens with AlCl3. Zn and Cu had antagonism relationship. The increase of Cu might attribute to the decrease of Zn. Cu facilitated the formation of reactive oxygen species that damaged DNA and chromatin (Linder, 2012). The overload of Cu would induce lipid peroxidation in the mitochondria of hepatocytes (Sokol et al., 1990). Zn was also an antioxidant and anti-inflammatory agent (Linder, 2012). Zn deficiency would induce oxidative injury and impair the membrane of hepatocytes. The oxidative stress in liver induced by Al was observed (Viezeliene et al., 2011). It indicates that Al affects hepatic Cu and Zn contents and induces oxidative stress in the liver. The latest evidence showed that Al might mediate Alzheimer’s disease through liver toxicity and the excess free Cu caused brain oxidation and -amyloid aggregation
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(Brenner, 2013). Zn was effective in attenuating the liver damage inflicted by Al toxicity (Bhasin et al., 2014). The reduction of Zn will decrease the function of hepatic detoxification. It suggests that AlCl3 induces oxidative stress by the reduction of Zn and the increase of Cu. In conclusion, the decreases of serum TP and ALB and hepatic Fe and Zn contents and the increases of serum TBI and DBI and hepatic Al and Cu contents indicate that the chronic administration of AlCl3 induces cumulative effect, damages hepatic metabolism function and disorders trace element distribution. Authors’ Note Ben Wang and Yanzhu Zhu contributed equally to this study. Jilin Science and Technology Vocational College and Institute of Special Animal and Plant Sciences of Chinese Academy of Agricultural Sciences, Changchun 130112, China, contributed equally to this study.
Funding The study was supported by a Grant from the National Science Foundation Project (31172375, 31302147), the Youth Station in Jilin Science and Technology Vocational College (01002) and Science Foundation for Young Scientists of Jilin Province (20130522091JH).
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