Chronic Exposure to Aroclor 1254 Disrupts Glucose Homeostasis in

Article pubs.acs.org/est

Chronic Exposure to Aroclor 1254 Disrupts Glucose Homeostasis in Male Mice via Inhibition of the Insulin Receptor Signal Pathway Shiqi Zhang,† Tian Wu,† Meng Chen,§ Zhizhun Guo,† Zhibin Yang,† Zhenghong Zuo,*,†,§ and Chonggang Wang*,†,‡ †

State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361006, P.R. China State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen 361006, P.R. China § Key Laboratory of Ministry of Education for Subtropical Wetland Ecosystem Research, Xiamen University, Xiamen 361006, P.R. China Downloaded by KTH ROYAL INST OF TECHNOLOGY on August 24, 2015 | http://pubs.acs.org Publication Date (Web): July 30, 2015 | doi: 10.1021/acs.est.5b01597

‡

S Supporting Information *

ABSTRACT: Epidemiological studies demonstrate that polychlorinated biphenyls (PCBs) induce diabetes and insulin resistance. However, the development of diabetes caused by PCBs and its underlying mechanisms are still unclear. In the present study, male C57BL/6 mice were orally administered with Aroclor 1254 (0.5, 5, 50, and 500 μg/kg) once every 3 days for 60 days. The body weight and the fasting blood glucose levels were significantly elevated; the levels of serum insulin, resistin, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) increased, while glucagon levels decreased in the animals treated with Aroclor 1254. Pancreatic β-cell mass significantly increased, while α-cell mass was reduced. Aroclor 1254 inhibited the expression of the insulin receptor signaling cascade, including insulin receptor, insulin receptor substrate, phosphatidylinositol 3-kinase-Akt, and protein kinase B and glucose transporter 4, both in the skeletal muscle and the liver. The results suggested that chronic exposure to Aroclor 1254 disrupted glucose homeostasis and induced hyperinsulinemia. The significant elevation of serum resistin, TNFα and IL-6 indicated that obesity caused by Aroclor 1254 is associated with insulin resistance. The elevation of blood glucose levels could have been mainly as a result of insulin receptor signals pathway suppression in skeletal muscle and liver, and a decrease in pancreatic α-cells, accompanied by a reduction of serum glucagon levels, may play an important role in the development of type 2 diabetes.

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INTRODUCTION The prevalence of diabetes mellitus is now reaching epidemic proportions. In addition to genetic predisposition and lifestyle choices, it is suggested that environmental pollutants are additional risk factors for diabetes development. Both epidemiological and experimental evidence indicate that some environmental pollutants are related to diabetes mellitus.1−3 Some epidemiologic observations reveal that people exposed to persistent organic pollutants (POPs) are linked to obesityrelated metabolic dysfunction such as insulin resistance, hyperinsulinemia, and diabetes mellitus and cardiovascular diseases.4,5 Widespread organic pollutants, such as dioxins, pesticides, and bisphenol A (BPA), cause insulin resistance and disrupt glucose homeostasis in animal models.6 POPs including polychlorinated biphenyls (PCBs) and organochlorine pesticides may be associated with type 2 diabetes risk via increasing insulin resistance.7 A Belgian study shows highly significant elevation of serum levels of dioxins and PCBs among patients with type 2 diabetes.8 A linear association between serum PCB levels and diabetes incidence in a large cohort in Michigan is observed.9 The specific molecular mechanisms associating © 2015 American Chemical Society

POPs and diabetes have been an area of extensive study in the past decade, but this association is still not fully understood. PCBs are a class of chlorinated compounds that have been released into the environment by human activity. Even when PCBs are banned, environmental PCB levels show just a slight decrease or even no decrease.10 Many researchers report PCBs in human blood and tissues around the world. For example, the mean concentration of three PCB congeners (PCB 138, 153, and 180) is 345.81 ng/g lipid in adipose tissue samples collected from Southern Spain.11 The PCB concentration in human blood is 70 ng/g lipid in Shanghai, China.12 The concentration of PCBs in serum of the general population of Bizerte, Tunisia, ranges from 37.5 to 284.6 ng/g lipid.13 These studies on human PCB burdens indicate that there is considerable risk from human exposure to PCBs. Received: Revised: Accepted: Published: 10084

March 30, 2015 June 23, 2015 July 18, 2015 July 18, 2015 DOI: 10.1021/acs.est.5b01597 Environ. Sci. Technol. 2015, 49, 10084−10092

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Downloaded by KTH ROYAL INST OF TECHNOLOGY on August 24, 2015 | http://pubs.acs.org Publication Date (Web): July 30, 2015 | doi: 10.1021/acs.est.5b01597

Environmental Science & Technology

ogy (Santa Cruz, CA), and all other chemicals were of analytical grade and were obtained from commercial sources. Animals and Treatments. All animal experiments were conducted following the research protocols approved by the Xiamen University Institutional Animal Care and Use Committee. Male C57BL/6 mice, aged 21 days and weighing 12−14 g, were purchased from the Center of Experimental Animals, Xiamen University, China, and housed at 22 ± 1 °C under a 12:12 h light−dark cycle, with free access to food and water. After the quarantine period (2 days), 65 mice with adequate weight gain and without adverse clinical signs were divided randomly into five experimental groups. These mice were administered with Aroclor 1254 by oral gavage once (0.5, 5, 50, and 500 μg/kg) every 3 days for 60 days; control mice received an equal volume of the vehicle (5 μL/g) (10% ethanol in 0.85% sodium chloride). Individual animals were weighed before gavage, and actual dosing volumes were adjusted based on the body weights recorded. Glucose Tolerance Test (GTT) and Analyses of Blood Glucose. After gavage for 60 days, 65 mice were fasted overnight for 14 h before administration of the GTT. D-Glucose was dissolved in ddH2O and injected into the fasted mice (2 g/ kg of body weight). Samples of whole blood (1−2 μL each) were collected from a tail-clip bleed immediately before and 30, 60, and 120 min after glucose administration. Blood glucose levels were measured using a hand-held glucometer (ACCUCHEK Aviva, Roche, Basel, Switzerland). Homeostasis model assessment-insulin resistance (HOMA-IR) was used as an index to measure the degree of insulin resistance, as calculated by the formula: HOMA-IR = insulin (mIU/L) × glucose (mmol/L) ÷ 22.5.25 Tissue Sampling and Histological Examination. To avoid the influence of glucose injection on the hormone levels, these mice were sacrificed 3 days (day 63) after GTT. The mice were fasted overnight for 14 h. Animals were then euthanized by intraperitoneal injection with sodium pentobarbital (60 mg/ kg). Before sacrifice, mice were weighed again. Blood samples were collected from the eye socket and then stored at −80 °C for analysis. Eight pancreases from each group were fixed in 10% neutral buffered formalin solution and then embedded in paraffin, cut into 4 μm sections, and stained with hematoxylin and eosin for histopathological study. Liver, skeletal muscle, and other pancreases were collected during necropsy, frozen in liquid nitrogen immediately, and then stored at −80 °C until analysis. Relative islet area was determined based on the reported method.26 For each individual, 10 areas from four different sections were randomly chosen for analysis under a light microscope at a magnification of ×100. The image analysis quantified total tissue area within this region, followed by islet area to generate the ratio of islet to total pancreas area. Determination of Hormones and Inflammatory Factors. We used an ELISA Kit to analyze the serum levels of insulin (Millipore, St. Charles, MO), glucagon (ELAab Science Co., Wuhan, China), resistin and adiponectin (SangonBiotech, Shanghai Co., Ltd.), TNFα (SangonBiotech, Shanghai Co., Ltd.), and interleukin-6 (IL-6) (SangonBiotech, Shanghai Co., Ltd.). Immunohistochemistry. Cellular distribution of insulin and glucagon was revealed by immunostaining using the streptavidin−peroxidase conjugate method.27 The antibodies used were anti-insulin (1:400 dilution) and antiglucagon (1:400 dilution). Staining was performed using stable diaminobenzidine solution. The sections were lightly counterstained with

Many epidemiological studies observe that associations exist between PCB exposure and obesity, metabolic syndrome, and diabetes.14 The mechanisms underlying the development of type 2 diabetes are complicated; the main cause is that the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of acquired β-cell secretory dysfunction or decreased β-cell mass.15 There is a relationship between the onset of diabetes and endocrine disruption caused by environmental chemicals. In 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD)-treated rats, insulin content is significantly decreased.16 Treatment with TCDD (100 μg/kg per day) for 10 days alters glucose tolerance,17 but a single dose of 10 μg/kg decreases only plasma insulin levels.18 TCDD at a dose as low as 0.03 μg/kg (single intraperitoneal) causes a significant reduction in the glucose transporting activity of guinea pig adipose tissue and pancreas.19 The exposure of adult mice to BPA disrupts pancreatic β-cell function in vivo and induces insulin resistance.20 Tributyltin exposure for 60 days reduces relative islet area and the levels of serum insulin or glucagon in mice.21 Everett et al., reviewing the relationship of PCBs with type 2 diabetes, point out that the mechanism underlying this connection is not well understood. However, the effects of PCBs on diabetes development are even less thoroughly studied and mechanistic information is sparser.22 Proposed mechanisms linking PCBs to the development of diabetes include glucose uptake reduction,23 insulin release induction, and increased adipose tumor necrosis factor (TNFα) expression.24 Further and ongoing studies are needed to fully elucidate if PCB exposure induces insulin resistance and diabetes and the underlying genetic and biochemical processes.22 Insulin regulates the primary blood glucose concentration by increasing glucose uptake in tissues such as skeletal muscle, liver, and adipose tissue. Insulin signaling is initiated by the binding of insulin to insulin receptor (IR), leading to phosphorylation/activation of insulin receptor substrate (IRS) proteins such as IRS1 and IRS2, which are associated with the activation of the phosphatidylinositol 3-kinase (PI3K)-Akt or protein kinase B (PKB) pathway. IRS1 activates PI3K, resulting in the generation of phosphatidylinositol 3,4,5-triphosphate at the plasma membrane. This activation of the PI3K pathway promotes membrane recruitment and activation of Akt and its downstream targets, which result in the translocation of glucose transporter 4 (GLUT4) to the plasma membrane, leading to increased glucose uptake in the tissues. However, there are no reports concerning PCBs affecting the IR pathway. In the present study, we investigated the effects of PCBs on glucose homeostasis and looked into the toxicological mechanism involved.

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MATERIALS AND METHODS Chemicals. Aroclor 1254 (a commercial PCB mixture) was obtained from SUPELCO, U.S.A. This was dissolved in 100% ethanol and diluted with 0.85% sodium chloride to produce stock concentrations of 0.1, 1, 10, and 100 μg/mL, and the final ethanol concentration was 10% (v/v). Rabbit anti-insulin, antiglucagon, and mouse IRβ antibodies were purchased from Cell Signaling Technology, Inc. (Danvers, MA). Rabbit phospho-IRS1 (p-IRS1), phospho-IR (p-IR), and PI3K antibodies were obtained from Abcam (Cambridge, U.K.). Rabbit IRα, anti-Akt, and antiphospho-Akt antibodies were purchased from Biosynthesis Biotechnology Co., Ltd. (Beijing, China). Rabbit anti-IRS1 antibodies were from Santa Cruz Biotechnol10085

DOI: 10.1021/acs.est.5b01597 Environ. Sci. Technol. 2015, 49, 10084−10092

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increased to 250 °C at a rate of 2 °C/min, followed by a rate of 25 °C/min to 300 °C, and then held for 15 min. The total run time was 53 min. The MS was operated in electron impact with selective reaction monitoring mode. Results were expressed as nanograms PCB congener per gram tissue. The PCBs were identified by selected ion and their retention times. The recovery efficiency ranged from 78% to 92%, and the limit of detection ranged from 0.2 to 0.8 ng/g. Quantification was achieved based on calibration curves obtained using PCB standards. PCB accumulation in tissues was calculated by multiplying the concentration of each PCB congener determined. Statistical Analysis. All data were expressed as mean ± SE. The data were statistically analyzed with one-way analysis of variance (ANOVA) using the SPSS software (SPSS Inc., Chicago, IL, U.S.A.), and significant differences of means between groups were examined using Duncan post hoc tests. A difference was considered significant with values of p < 0.05.

hematoxylin. The experiments were repeated several times, and negative control sections omitting the addition of primary antibodies were run in parallel. For each individual, four different sections were randomly chosen for analysis. To count the numbers of cells positive for insulin and glucagon in the pancreas, approximately 20 islet cells were randomly selected from four different areas in each section and examined under a light microscope at a magnification of ×400. The percentage of positive cells (positive cells/total cells ×100%) was calculated. Relative αand β-cell area and mass were calculated based on the reported method.27 Western Blot Analysis. Protein was extracted from the frozen tissue using homogenization, and fraction samples (40 μg proteins) were mixed with 5× Coomassie brilliant blue and heated to 100 °C in a water bath for 5 min. A 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDSPAGE) was performed at a constant voltage of 80 V for 1.5 h. After SDS-PAGE, the proteins were transferred to a nitrocellulose membrane and blocked at room temperature for 2 h in TBS buffer containing 5% nonfat dried milk to prevent nonspecific binding of reagents and then incubated overnight at 4 °C with antibodies against IRα (1:500), IRβ (1:500), IRS1 (1:1000), p-IRS1 (1:1000), p-IR (1:1000), PI3K (1:1000), Akt (1:500), and p-Akt (1:500). The membrane was washed three times in TBST for 15 min and incubated with a secondary antibody (1:10000) for 1 h at room temperature. Then, the membrane was washed three times in TBST, and the antibody-reactive bands were revealed using chemiluminescence (Sigma, U.K.). The intensity of bands was quantified using Quantity One software (Bio-Rad, U.S.A.). Determination of PCBs in Mice Livers or Skeletal Muscle. A total of 1 g of tissue from three individuals was pooled into a subsample, and four subsamples from each treatment were measured. We used selective pressurized liquid extraction (SPLE) to isolate PCBs. SPLE was conducted using a fully automated ASE 350 system (Dionex Corporation, Sunnyvale, CA). Briefly, the 1 g of tissue sample was freezedried, ground into fine powder, spiked with organic standards (the 13C labeled PCB-101), and left for 1 h to allow the solvent to mix thoroughly, before extraction. An extraction cell was loaded by inserting one filter paper (Dionex, Leeds, U.K.) into the cell outlet followed by 10 g of activated silica inserted with 2 g of anhydrous sodium sulfate, followed by another filter paper. The tissue powder mentioned above was then added, followed by 0.5 g of sand, which had been heated in a muffle furnace at 550 °C overnight. Extraction cells were prepared in triplicate and inserted into the cell tray for extraction. We used an extraction solvent (n-hexane: dichloromethane, 1:1, v/v) to extract these target compounds from the spiked liver samples. The extraction was carried out using the program under 80 °C, 10.3 MPa, three cycles, and 5 min. After extraction, the solvents were evaporated down to 1 mL under a gentle stream of nitrogen gas, and then, 50 ng of internal standard PCB-103 was added. Concentrations of PCBs were determined using a Varian 1200 gas chromatography-mass-mass spectrometer (GC-MS/ MS) system (CP-3800 GC; Varian, Walton-on Thames, U.K.) with an HP-5MS 5% phenyl methyl siloxane column (30 m length, 0.25 mm internal diameter, 0.25 μm film thickness). The GC injector temperature was 280 °C with splitless mode, and the GC oven temperature was programmed as follows: 60 °C for 2 min, increased 20 °C/min to 200 °C, held for 2 min,

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RESULTS Aroclor 1254 Increased Body Mass and Weight Gain. When animals were treated with Aroclor 1254 for 63 days, their body weight and body weight gain increased in a dosedependent manner and reached a significant difference in the 500 μg/kg group compared to the control (Figure 1A; Supporting Information (SI), Figure S1). Aroclor 1254 Results in Glucose Intolerance and Hyperglycaemia. We used fasting blood glucose, 2 h GTT, and HOMA-IR to evaluate glucose homeostasis and tolerance. Overnight fasting blood glucose levels were elevated in a dosedependent manner after treatment with Aroclor 1254 for 60 days and showed a significant increase in the 50 and 500 μg/kg group compared to the control (Figure 1B). The GTT results showed that the treatment with Aroclor 1254 (5, 50, and 500 μg/kg) resulted in a significant increase in blood glucose concentrations compared with the control, in response to a bolus of administered glucose (Figure 1C). We calculated the area under the GTT curve (AUC) for all treatment groups in order to quantify glucose tolerance. The AUC values were increased in a dose-dependent manner and were significantly elevated in the 5, 50, and 500 μg/kg groups (SI, Figure S2). To further evaluate whether the mice had insulin resistance after treatment with Aroclor 1254, we used fasting blood glucose and fasting serum insulin to calculate HOMA-IR, an indicator of insulin resistance. The average HOMA-IR values were elevated in a dose-dependent manner, and similarly, the values were significantly increased in the 5, 50, and 500 μg/kg groups compared with the control (SI, Figure S3). Aroclor 1254 Disturbed Serum Hormone Levels. The fasting serum insulin levels increased in a dose-dependent manner and reached a significant difference in the 500 μg/kg group, whereas fasting serum glucagon levels were decreased significantly in the 50 and 500 μg/kg groups compared to the control (Figure 2A and B). The levels of serum resistin, adiponectin, TNFα, and IL-6 were elevated in a dosedependent manner (Figure 2C, D, E, and F). Aroclor 1254 Affected Islet Cell Mass. Immunohistochemical staining with insulin-specific antibody showed that insulin positive cells were located in the central regions with high frequency in the islets but with no marked changes (SI, Figure S5A), and glucagon labeling showed peripheral staining with a discontinuous ring pattern (SI, Figure S6A). It was observed that the relative islet area significantly increased as the 10086


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Figure 2. Effect of Aroclor 1254 on serum hormone levels in mice exposed for 63 days. The mice were fasted overnight for 14 h. (A) Insulin levels. (B) Glucagon levels. (C) Adiponectin levels. (D) Resistin levels. (E) TNFα levels. (F) IL-6 levels. All data are shown as mean ± SE; (A−D) n = 11−13. (E−F) n = 6. Data were analyzed using ANOVA followed by the Duncan test. Means of exposures not sharing a common letter are significantly different at p < 0.05.

Aroclor 1254 Down-Regulated the Insulin Receptor Pathway in Skeletal Muscle and Liver. Aroclor 1254 treatment resulted in a decrease in the IR-IRS1-PI(3)K-AktGLTU4 signaling cascade, including their phosphorylation, in both skeletal muscle (Figure 5A) and liver (Figure 5B), which regulate glucose absorption in these tissues. It was observed that the reduction of protein expression was more evident in the skeletal muscle than in the liver. PCB Accumulation in Liver or Skeletal Muscle. Several dominant PCBs were determined. The sum of these PCBs was used to indicate the accumulation of Aroclor 1254 in the liver or muscle. The PCB levels in the both tissues increased in a dose-dependent manner and reached a significant difference in the 50 and 500 μg/kg groups (SI, Table S1). The accumulation of PCB was much higher in the liver than in the muscle.

Figure 1. Aroclor 1254 impaired glucose tolerance and increased body mass in male mice exposed for 63 days. (A) Body weight gain. (B) Fasting glucose levels. (C) Glucose intolerance test (GTT). All data are shown as mean ± SE n = 13. Data were analyzed using ANOVA followed by the Duncan test. Means of exposures not sharing a common letter are significantly different at p < 0.05. The comparisons were made within a time point in panel C.

Aroclor 1254 doses increased (SI, Figure S4). β-cell mass and β-cell density in the islet significantly increased. The highest elevation of β-cell mass or β-cell density both occurred in the 500 μg/kg group (Figure 3A, B, and C), while relative α-cell area and α-cell mass were significantly decreased in the Aroclor 1254-treated pancreas. The density of α-cell was decreased in a dose-dependent manner and reached a significant difference in the 5, 50, and 500 μg/kg groups (Figure 4A, B and C). The mean density values of insulin and glucagon were analyzed using Image-Pro-Plus software in order to further determine the expression of insulin and glucagon in the Aroclor 1254treated pancreas. Expression of insulin was not significantly changed by Aroclor 1254 exposure (SI, Figure S5), while the mean density of glucagon was significantly decreased by Aroclor 1254 exposure (SI, Figure S6).

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DISCUSSION In Asia, the average PCB concentration in fish and shellfish is 3.60 ng/g ww, with a range of 0.83−8.04 ng/g ww.28 PCB concentrations in seafoods are in the range 0.20 ng/g (shrimp) to 2.5 ng/g wet weight (horse mackerel) around Shanghai, China.12 The level of PCBs in Perna viridis collected in Xiamen Island, China, is 65.2 ng/g dry weight, 29 and PCB concentrations range from 6.3 to 199 ng/g lipid weight in marine fish collected from Yongxing Island, in the South China Sea.30 The contributions of fish and other seafood to total daily dietary intake of PCBs are 55%. Using an average seafood 10087


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Figure 4. Effects of Aroclor 1254 on α-cell in male mice exposed for 63 days. (A) Cellular distribution of glucagon positive cells in the islets: (a) control, (b) 0.5 μg/kg, (c) 5 μg/kg, (d) 50 μg/kg, and (e) 500 μg/kg. Glucagon positive cells are indicated by brown staining. Asterisks indicate islets of Langerhans. Scale bar = 200 μm. (B) Relative α-cell area and α-cell mass. (C) α-cell density in islets. Data are presented as mean ± SE (n = 4). Means of exposures not sharing a common letter are significantly different at p < 0.05 as assessed by oneway ANOVA followed by the Duncan test. The comparisons were made within the groups of relative α-cell area or α-cell mass in panel B.

Figure 3. Effects of Aroclor 1254 on β-cell in male mice exposed for 63 days. (A) Cellular distribution of insulin positive cells in the islets: (a) control, (b) 0.5 μg/kg, (c) 5 μg/kg, (d) 50 μg/kg, and (e) 500 μg/ kg. Insulin positive cells are indicated by brown staining. Asterisks indicate islets of Langerhans. Scale bar = 200 μm. (B) Relative β-cell area and β-cell mass. (C) β-cell density in islets. Data are presented as mean ± SE (n = 4). Means of exposures not sharing a common letter are significantly different at p < 0.05 as assessed by one-way ANOVA followed by the Duncan test. The comparisons were made within the groups of relative β-cell area or β-cell mass in panel B.

consumption of 0.164 kg/day,31 the total daily dietary intakes of PCBs in e-waste disassembly sites are estimated to be 12,372.9 ng/day in the Zhejiang province of China.30 Data from Gray et al.32 indicate that an Aroclor 1254 dose of 36 mg/ kg/wk represents a chronic, high-level environmental exposure. Doses of Aroclor 1254 ranging from 0.5 to 500 μg/kg used in 10088


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Figure 5. Western blot analysis of IRα, IRβ, phospho-IR, IRS-1, phospho-IRS-1, PI(3)K, Akt, phospho-Akt, and Glut 4 proteins in the skeletal muscle and liver of male mice exposed to Aroclor 1254 for 63 days. Representative chemiluminescence detection of protein expression in skeletal muscle (A) and liver (B). Intensities of target protein bands were quantified by densitometry in skeletal muscle (a) and liver (b). Results are expressed as folds of optical density of target protein and the GAPDH or β-actin determined in the control. The mean protein expression from the control was designated as 1 in the graph. Data are presented as mean ± SE (n = 4). Data were analyzed using ANOVA followed by the Duncan’s test. Means of exposures not sharing a common letter are significantly different at p < 0.05. The comparisons were made within the groups of a protein.

skeletal muscle and adipose tissue.38 Orally administered coplanar PCB, PCB-77, or PCB-126 for 2−12 weeks in lean mice induces insulin insensitivity independent of changes in body weight,24 which are supported by the results of Gray et al.32 To our knowledge, the present study demonstrated for the first time that Aroclor 1254 can suppress in vivo the insulin signaling pathway in both skeletal muscle and liver. In the present study, we did not determine the expression of insulin signaling in adipose tissue since the visceral fat was very little and not enough for analysis. Because the skeletal muscle and liver are responsible for 70−90% of insulin-stimulated glucose disposal,39 the results from these two tissues could explain the impairment of Aroclor 1254 on blood glucose levels. The reduction of insulin signaling in skeletal muscle and liver is an important reason for hyperglycemia. The inhibition of Aroclor 1254 on the IR pathway would be a indirect effect since the PCB accumulation was much less in the skeletal muscle than in the liver, while the inhibition in the skeletal muscle was more evident. Obesity is the most common cause of insulin resistance and type 2 diabetes. Adipose tissue can excrete several metabolism related hormones, such as leptin, adiponectin, resistin, and TNF. Several studies have consistently reported a close relationship between resistin levels and obesity, insulin resistance, or type 2 diabetes.40 Resistin induces insulin resistance when injected into normal mice,41 and resistin may

the present study were in accord with the PCB intake estimated for humans. There are some reports concerning the toxicological effects of PCBs on obesity-induced insulin resistance in animals. Aroclor 1254 (36 mg/kg/wk) exposure causes hyperinsulinemia in both lean and diet-induced obese mice and exacerbates whole-body insulin resistance in obese mice.32 PCB 153 (50 mg/kg/wk) treatment in high-fat-fed mice is associated with increased visceral adiposity, hepatic steatosis, and plasma adipokines including adiponectin, leptin, resistin, and plasminogen activator inhibitor-1 levels in mice.33 PCB 77 (50 mg/ kg) or PCB 126 (1.6 mg/kg) significantly impairs glucose tolerance and insulin tolerance in mice.24 The results in the present study demonstrated that chronic Aroclor 1254 exposure at low doses also caused obesity and hyperglycaemia in mice. Insulin resistance in skeletal muscle, adipose tissue, and liver probably has a central role in the pathogenesis of type 2 diabetes.34 The reduction of insulin signaling plays an essential role in the pathogenesis of glucose intolerance.35 The musclespecific IR knockout mice exhibit an altered fat metabolism associated with type 2 diabetes.36 Mice with mutations in the IRs IRS1 and IRS2 exhibit insulin resistance in peripheral tissues and liver and impaired glucose tolerance.37 Rats fed crude, PCB-containing fish oil are insulin resistant, due to hepatic insulin resistance and impaired glucose uptake in 10089


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increase in β-cell mass appeared to compensate for the increased metabolic load and insulin resistance. However, the effect of Aroclor 1254 exposure for a longer time on β-cell mass awaits further investigation. The islets of Langerhans are mainly composed of two different hormone-producing cell types: β-cells producing insulin and α-cells producing glucagon. The main physiological role of glucagon is to stimulate hepatic glucose output, increasing glycemia. There are many studies reporting the effect of pollutants on β-cells, but rarely on α-cells. In the present study, the serum glucagon levels decreased, and the mean density of glucagon in the islets decreased in mice treated with Aroclor 1254, as revealed by immunohistochemistry, indicating a reduction of glucagon synthesis, while the reduction of α-cell mass was the main reason for the decreased serum glucagon in the Aroclor 1254-treated mice. To our knowledge, the present study observed for the first time that Aroclor 1254 exposure decreased α-cells in the islets, which would lead to a failure of the pancreatic α-cells counterregulation with insulin to maintain the glucose homeostasis in blood since glucagon is a primary regulator of hepatic glucose production in vivo during fasting, exercise, and hypoglycemia. In some individuals, dysregulation of glucagon secretion can be proximate to the development of diabetes.59 The lack of a glucagon response to hypoglycemia in juvenile diabetes suggests an intrinsic pancreatic α-cell defect.60 The decrease in α-cells could be one of the reasons causing the lack of glucagon response to hypoglycemia. Furthermore, the decrease in α-cells may result in an absence of a new generation of βcells when the β-cells are nearly a total loss since pancreatic αcells can transform and transdifferentiate into β-cells after extreme β-cell loss.61 The results in the present study demonstrated that chronic exposure to Aroclor 1254 disrupted glucose homeostasis. The levels of insulin increased accompanied by a significant elevation of serum resistin, TNFα, and IL-6, indicating that obesity caused by Aroclor 1254 was associated with insulin resistance. The elevation of blood glucose levels could mainly have been a result of IR signal pathway suppression in skeletal muscle and liver. A decrease in pancreatic α-cells may play an important role in the development of type 2 diabetes, and it is suggested that the failure of diabetics to respond to hypoglycemia may be due to an absence of pancreatic αcells.60 This was supported by the results in our study. These results should be helpful in understanding the development of diabetes mellitus caused by PCBs.

be a factor secreted by adipocytes that links type 2 diabetes and insulin resistance.42 Chronic “hyper-resistinemia” leads to whole-body insulin resistance involving impaired insulin signaling in skeletal muscle, liver, and adipose tissue, resulting in glucose intolerance, hyperinsulinemia, and hypertriglyceridemia.43 TNF-α is a contributor to insulin resistance44 and promotes insulin resistance through downstream alternative phosphorylation of the IR docking protein, IRS1, which prevents phosphorylation of Akt (or PKB) and impairs transport of GLTU4 vesicles in skeletal muscle and adipose tissue to the plasma membrane.24 Overexpression of TNFα in fat and muscle cells induces insulin resistance by increasing the serine phosphorylation of IRS1 and IRS2, resulting in a reduction in the ability of the IRS molecules to dock with receptors and interact with downstream pathways, such as PI3K and glucose transport.45 IL-6 also plays an important role in the induction of insulin resistance. IL-6, like TNFα, exerts longterm inhibitory effects on the gene transcription of IRS1, GLUT4 in 3T3-L1 adipocytes, accompanied by a marked reduction in insulin-stimulated glucose transport.46 IL-6-treated adipocytes show a decreased protein expression of the IRβ subunit and IRS1 but also an inhibition of the insulin-induced activation of IRβ, Akt/PKB, and ERK1/2. Moreover, IL-6 suppresses insulin-induced lipogenesis and glucose transport consistent with a diminished expression of GLUT4.47 The chronic elevation of IL-6 circulating levels contributes to wholebody insulin resistance, particularly in liver and adipose tissue.48 Coplanar PCBs increase the abundance of TNFα mRNA in cultured adipocytes.49 PCB-77 (2.5, 50, or 248 mg/kg week) treatment increases adipose TNFα expression and insulin resistance in mice.24 In the present study, Aroclor 1254 caused glucose intolerance and hyperinsulinemia associated with the elevation of serum resistin, TNFα, and Il-6 levels. Adiponectin possesses anti-inflammatory, insulin-sensitizing, and antidiabetic activities. Treatment with adiponectin increases insulin sensitivity in animal models.50 Adiponectin can strengthen insulin sensitivity by upregulating hepatic IRS2 expression via an IL-6 dependent pathway.51 Adiponectindeficient mice show mild insulin resistance with glucose intolerance.52 In skeletal muscle, adiponectin causes an increase in glucose uptake through promotion of GLUT4 translocation to the plasma membrane.53 However, exposure to PCB 153 causes a significant increase in resistin and adiponectin levels in male C57BL6/J mice fed a high-fat diet.54 In the present study, elevation of the serum adiponectin levels occurred in mice exposed to Aroclor 1254, which might be a consequence due to the adaptation of their body’s response to insulin resistance. Environmental pollutants can induce insulin secretory dysfunction.55 β-cell mass in the adult is plastic, and adjustment in β-cell growth and survival maintains a balance between insulin supply and metabolic demand.15 Initially, a normal glucose level is maintained through hyperinsulinemia, which compensated for insulin resistance,56 whereas this β-cell adaptation eventually fails to compensate for insulin resistance, and type 2 diabetes occurs.15 Rats exposed to PCB develop abnormal β-cell morphology, indicative of increased β-cell activity.57 Increased demand for insulin including hyperglycaemia, insulin resistance, obesity, and pregnancy results in larger β-cell mass in young rodents.58 In the present study, exposure to Aroclor 1254 caused an elevation of serum insulin levels, which indicated the occurrence of insulin resistance. Increased β-cell mass in animals treated with Aroclor 1254 was consistent with the elevation of serum insulin levels. An

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ASSOCIATED CONTENT

* Supporting Information S

Additional one table and six figures showing the exposure effects. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.est.5b01597.

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AUTHOR INFORMATION

Corresponding Authors

*Phone: +86 592 2187353. E-mail: [email protected]. cn (Zhenghong Zuo). *Phone: +86 592 2187353. E-mail: [email protected] (Chonggang Wang). Notes

The authors declare no competing financial interest. 10090


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ACKNOWLEDGMENTS The project was supported by the National Key Technology R&D Program of China (2007BAC27B02) and the Project 111 of the Ministry of Education (Grant B06016). Professor John Hodgkiss is thanked for his assistance with the English in our paper.


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Chronic Exposure to Aroclor 1254 Disrupts Glucose Homeostasis in

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